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PegIntron with or without 3TC for Hepatitis B Treatment
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Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial
Harry L A Janssen, Monika van Zonneveld, Hakan Senturk, Stefan Zeuzem, Ulus S Akarca, Yilmaz Cakaloglu, Christopher Simon, Thomas M K So, Guido Gerken, Robert A de Man, Hubert G M Niesters, Pieter Zondervan, Bettina Hansen, Solko W Schalm, for the HBV 99-01 Study Group*
Lancet 2005; 365: 123-29
BRIEF HIGHLIGHTS
--The current standard initial therapy for patients with chronic HBV infection is interferon alfa, lamivudine, or adefovir dipivoxil
--The introduction of pegylated interferons, with their better pharmacokinetic profiles, has led to higher response rates in chronic hepatitis C,25,26and a preliminary study suggested improvements in the response rates in HBeAg-positive patients with chronic hepatitis B
--Treatment with pegylated interferon alfa-2b and lamivudine combination therapy was superior to monotherapy at the end of treatment, but not at the end of follow-up.
--307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 microgram/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 microgram/week pegylated interferon alfa-2b and placebo) for 52 weeks.
--During weeks 32--52 the pegylated interferon dose was 50 microgram/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment.
--Results: 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0·91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0·01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase.
--Response rates (HBeAg loss) varied by HBV genotype (p=0·01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%).
--Our study reveals prospectively the importance of HBV genotype as an independent predictor of response to pegylated interferon treatment for chronic hepatitis B. It accords with earlier retrospective studies, which indicated that HBV genotypes C and D are more difficult to treat than genotypes A and B
--The side-effects and frequency of adverse events observed with pegylated interferon alfa-2b monotherapy were similar to those encountered with standard interferon therapy. The rates of dose reductions and discontinuations were similar to those reported with pegylated interferons in patients with chronic hepatitis C,16,25,26 and with pegylated interferon alfa-2a in chronic hepatitis B.
--Rates of sustained clearance of serum HBeAg and reduction of viral load are as high as or higher than those that have previously been reported for any other therapy in this indication. Combination therapy with pegylated interferon alfa-2b and lamivudine is not superior to monotherapy with pegylated interferon alfa-2b.
Authors:Departments of Gastroenterology and Hepatology (H L A Janssen MD, M van Zonneveld MD, R A de Man MD, B Hansen MD, S W Schalm MD), Virology (H G M Niesters PhD), Pathology (P Zondervan MD), and Biostatistics (B Hansen MSc); Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Departments of Internal Medicine (H Senturk MD) and Gastroenterohepatology (Y Cakaloglu MD), Cerraphasa Medical Faculty, University of Istanbul, Istanbul, Turkey; Department of Medicine, Division of Gastroenterology, Hepatology, and Endocrinology, Saarland University Hospital, Homburg/Saar, Germany (S Zeuzem MD); Department of Gastroenterology, Ege University Hospital, Izmir, Turkey (U S Akarca MD); Department and Clinic of Infectious Diseases, Medical University, Wroclaw, Poland (C Simon MD); Department of Medicine, Princess Margaret Hospital, Hong Kong, China (T M K So MD); and Department of Gastroenterology and Hepatology, University Hospital Essen, Germany (G Gerken MD)
Summary/Abstract
Background: Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response.
Methods: 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 µg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 µg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32-52 the pegylated interferon dose was 50 µg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment.
Findings: 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0·91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0·01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0·01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%).
Interpretation: Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.
At the end of treatment, 242 (91%) of the 266 patients remained on treatment and 184 (69%) remained on full-dose treatment. There were no significant differences in dose reductions between the treatment groups.
Author Discussion
The current standard initial therapy for patients with chronic HBV infection is interferon alfa, lamivudine, or adefovir dipivoxil.23,24 The introduction of pegylated interferons, with their better pharmacokinetic profiles, has led to higher response rates in chronic hepatitis C,25,26and a preliminary study suggested improvements in the response rates in HBeAg-positive patients with chronic hepatitis B.17
In this large, randomised study, the rate of sustained response (HBeAg loss) in HBeAg-positive patients with chronic hepatitis B assigned pegylated interferon alfa-2b monotherapy was 36% (49 of 136 patients). Treatment with pegylated interferon alfa-2b and lamivudine combination therapy was superior to monotherapy at the end of treatment, but not at the end of follow-up.
Two previous randomised controlled trials comparing combination therapy and standard interferon monotherapy in chronically HBV-infected patients positive for HBeAg had a shorter duration of lamivudine therapy in the group assigned combination therapy than in the group assigned monotherapy.5,19 This feature and the timing of the primary efficacy endpoint (after treatment for combination therapy or interferon alone versus on-treatment for lamivudine alone) precluded a definitive conclusion on the efficacy of combination therapy. The investigators concluded that the potential benefit of combining lamivudine with interferon therapy should be investigated further with different regimens of combination therapy.
Our study advanced these investigations and helped progress towards a definitive conclusion on the efficacy of combination therapy versus monotherapy in two ways. First, it compared equivalent durations of treatment in the two groups. Second, the long follow-up period extended further beyond the end of treatment with lamivudine than in previous studies, which enabled the extent of relapse to be monitored after 26 weeks of follow-up.
Our study highlights differences in response to interferon and to nucleoside analogues. Although patients initially responded to lamivudine, the responses (HBeAg loss and HBV DNA reduction) were not sustained. This finding accords with those of previous studies, with HBeAg relapse rates of 49% to 54%.12,27 Lack of durability could be due to the mechanism of action of lamivudine, which suppresses viral replication without inducing the HBV-specific immune response necessary for sustained viral eradication.
Long-term therapy with lamivudine is not an option because it leads to drug resistance in most cases.23,28 The lack of this option is particularly difficult for patients with chronic hepatitis B, because many patients develop the disorder when quite young and have to be treated for several decades with resistance-prone medication for which long-term toxicity is unknown. A study with the nucleotide analogue adefovir dipivoxil suggested that response was achieved with development of phenotypic resistance in less than 1·6% of the patients.10 Future studies are needed to find out whether this response is sustained beyond the end of therapy and whether, with continued therapy, clinically relevant drug resistance remains absent.
Our study reveals prospectively the importance of HBV genotype as an independent predictor of response to pegylated interferon treatment for chronic hepatitis B. It accords with earlier retrospective studies, which indicated that HBV genotypes C and D are more difficult to treat than genotypes A and B.29,30 Future intervention studies for chronic hepatitis B might need stratification according to genotype.
The side-effects and frequency of adverse events observed with pegylated interferon alfa-2b monotherapy were similar to those encountered with standard interferon therapy. The rates of dose reductions and discontinuations were similar to those reported with pegylated interferons in patients with chronic hepatitis C,16,25,26 and with pegylated interferon alfa-2a in chronic hepatitis B.17
Pegylated interferon alfa-2b is effective and well tolerated for chronic hepatitis B. Rates of sustained clearance of serum HBeAg and reduction of viral load are as high as or higher than those that have previously been reported for any other therapy in this indication. Combination therapy with pegylated interferon alfa-2b and lamivudine is not superior to monotherapy with pegylated interferon alfa-2b.
Introduction
Patients successfully treated for chronic hepatitis B are less likely to develop cirrhosis, liver failure, and hepatocellular carcinoma than those who do not respond to treatment.1,2 However, to date, treatment for chronic hepatitis B has been unsuccessful in the majority of patients. Of the few currently approved agents for treatment of chronic infection with hepatitis B virus (HBV), the most commonly used are interferon alfa and nucleoside or nucleotide analogues, such as lamivudine and adefovir dipivoxil.
In early studies, use of standard (non-pegylated) interferon alfa reportedly cleared HBeAg and HBV DNA in about a third of treated patients.3,4 Subsequently, response rates of only 19% have been noted.5 HBeAg clearance induced by interferon alfa has been reported to be durable in 80-90% of patients, and the clearance is associated with a reduction in rates of hepatocellular carcinoma and death.1,6-8
Inhibitors of DNA polymerase, of which lamivudine and adefovir dipivoxil are currently the most effective and most studied, achieve profound reductions in viral load.9,10 However, sustained response after discontinuation of treatment is as yet unknown for adefovir dipivoxil and occurs in only 10-15% of patients treated with lamivudine.11 Responses to lamivudine are significantly less durable than that those to interferon alfa.12 Furthermore, the long-term efficacy of nucleoside analogues is compromised by the almost inevitable emergence of drug-resistant HBV mutants.13 Lamivudine resistance has been reported in 57% of patients after 3 years of treatment.14
There is increasing evidence that only a complete and vigorous HBV-specific immune response can achieve control and elimination of the virus, preventing disease progression.15 This evidence suggests that sustained response to HBV treatment requires induction of a host immune response, which can only be achieved with immunomodulatory therapy, such as interferon.
The introduction of pegylated interferons in the treatment of hepatitis C has led to greater treatment efficacy than is achieved with standard interferon,16 and a preliminary study has been done in the treatment of HBeAg-positive chronic hepatitis B.17 The better efficacy of pegylated interferons could be due to more constant concentrations in the serum than are achieved with standard interferon. These features are combined with a similar safety profile and simpler and more convenient dosing (once weekly) than with standard interferon (three times per week). The convenience of dosing is important because, across the therapeutic range, simpler dosing regimens improve adherence, which in turn increases treatment efficacy.18
To date, most studies of standard interferon combination regimens for the treatment of chronic HBV disease have investigated the efficacy of 16-week regimens.5,19 However, longer regimens might result in higher rates of sustained response.20 Our study is based on the rationale that combination of the immunomodulatory properties of interferon and the strong antiviral potency of lamivudine in a long-term treatment regimen might increase the rate of sustained response in chronic hepatitis B.
Methods
Participants
Patients with chronic hepatitis B aged 16 years or older were enrolled after assessment of their eligibility at the trial coordinating centre. Eligible patients had been positive for HBsAg for longer than 6 months; were positive for HBeAg on two occasions within 8 weeks before randomisation; and had had two episodes of raised serum concentrations of alanine aminotransferase (ALT; twice the upper limit of normal) within the 8 weeks before randomisation.
Reasons for exclusion were: presence of serum antibodies against hepatitis C virus, hepatitis D virus, or HIV; antiviral therapy or immunosuppressive therapy within the preceding 6 months; pregnancy or inadequate contraceptive measures; substance abuse during the previous 2 years; other acquired or inherited causes of liver disease; coexisting serious medical or psychiatric illness; uncontrolled thyroid disease; inadequate counts of leucocytes (le3x109/L), granulocytes (le1·8x109/L), or platelets (le100x109/L); radiological or imaging evidence of hepatocellular carcinoma; or advanced liver disease with a prothrombin time prolonged by more than 3 s, serum albumin concentration less than 35 g/L, bilirubin more than 35 µmol/L, or a history of ascites, variceal bleeding, or hepatic encephalopathy.
Study design
This investigator-initiated, randomised, double-blind, controlled trial was carried out at 42 centres in 15 countries in Europe, East Asia, and North America. Recruitment began in February, 2000, and the study ended in October, 2003. The study compared the efficacy and safety of pegylated interferon alfa-2b monotherapy and of combination therapy of pegylated interferon alfa-2b and lamivudine for treatment of patients with HBeAg-positive chronic hepatitis B.
Patients were randomly assigned in a one-to-one ratio to receive combination therapy with weekly doses of 100 µg pegylated interferon alfa-2b (PegIntron, Schering-Plough, Kenilworth, NJ, USA) and a daily dose of 100 mg lamivudine (Zeffix, GlaxoSmithKline, Greenford, UK) or monotherapy with 100 µg/week pegylated interferon alfa-2b and placebo, which was similar in appearance to lamivudine and was for daily administration. The total duration of treatment was 52 weeks. To limit the probability of early treatment discontinuation, the dose of pegylated interferon was lowered to 50 µg/week in both treatment groups after 32 weeks. Patients of bodyweight 55 kg or less received weight-adjusted dosing of pegylated interferon alfa-2b (1·50 µg/kg weekly for the first 32 weeks and 0·75 µg/kg weekly for the remainder of the treatment period). All patients were followed up for 26 weeks after treatment. During treatment and follow-up, patients attended outpatient clinics every 4 weeks for routine examination and laboratory tests.
Randomisation was done centrally and stratified by study centre. Treatment was allocated in blocks of six per centre. The study was conducted in accordance with good clinical practice and the Declaration of Helsinki, and it was formally approved by the ethics committee of each participating centre. Patients were required to give written, informed consent before joining the study. All centres were monitored by an independent company. Monitoring led to withdrawal of one centre, where source data could not be verified and all samples were thawed for a long period, precluding central assessment of primary and secondary endpoints (HBeAg and HBV DNA). The principal investigator of that centre resigned from his position for reasons unrelated to this study. Withdrawal took place during the course of the study by unanimous decision of the project coordinators and the biostatistician.
Outcome measures were assessed at the end of treatment (week 52) and at the end of follow-up (week 78). All HBV markers were assessed at the central laboratory at Erasmus MC, University Medical Center, Rotterdam by staff unaware of treatment allocation. The primary outcome measure was loss of HBeAg from serum, as tested by EIA (AxSYM, Abbott, Abbott Park, IL, USA). Secondary outcome measures were concentrations of HBV DNA below 200000 copies per mL, concentrations of HBV DNA below the level of detection (400 copies per mL by in-house Taqman PCR assay based on the Eurohep standard21), return to normal of ALT concentrations, and the presence of mutations in the YMDD motif of HBV polymerase (Inno-Lipa assay; Innogenetics, Ghent, Belgium). HBsAg (AxSYM, Abbott) and HBV genotype (Inno-Lipa assay, Innogenetics) were also assessed.
Routine biochemical and haematological tests were done at the participating centres by automated techniques. To correct for heterogeneity of local assays, serum concentrations of ALT were expressed as values representing a ratio to the local upper limit of normal.
Liver histology was assessed at baseline, and an optional biopsy sample was taken at the end of treatment. The samples were scored centrally by one experienced pathologist who was not aware of treatment regimen or the chronological order of the samples. Histological scoring was done according to the histological activity index.22 Improvement in histology was defined as a decrease of at least 2 points for the necroinflammatory score (range 0-18) and 1 point for the fibrosis score (range 0-6).
Statistical analysis
The study was powered to account for a mixed population with 50% of patients previously non-responsive to interferon therapy and 50% who had not received interferon previously, with a baseline ALT concentration of more than twice the upper limit of normal. To obtain a power of more than 80% (alpha=0·05), an estimated 270 patients would be needed, on the assumption of rates of HBeAg loss at the end of follow-up of 20% for pegylated interferon monotherapy and 36% for lamivudine combination therapy. The sample-size calculation was based on an estimated withdrawal rate of 20%; withdrawals were to be classified as treatment failures. Analyses were based on the modified intention-to-treat population--ie, all randomised patients who met the inclusion criteria and who received at least one dose of study medication.
The effects of pegylated interferon alfa-2b monotherapy and combination therapy with lamivudine on response rates were compared by the chi2 test. Response rates are those assessed by percentage HBeAg loss, HBV DNA concentration below 200 000 copies per mL, HBV DNA negative by PCR, or normal ALT concentrations at the end of treatment and the end of follow-up. Patients with missing data at week 52 or week 78 were classified as non-responders at end of treatment or the end of follow-up, respectively.
The relation between characteristics of patients at baseline and HBeAg loss at the end of follow-up (sustained response) was examined by logistic regression analyses. Univariate analysis was used to assess the importance of prognostic factors. To check the independence of these factors, multiple logistic regression analyses were done with all baseline characteristics given in table 1. All p values were two sided.
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Role of the funding source
The study was organised and sponsored by the Foundation for Liver Research, Rotterdam, the Netherlands. Financial support, study medication, and drugs were provided by Schering-Plough International and GlaxoSmithKline Research and Development. Companies providing financial support to the Foundation for Liver Research approved the study design. No funding source had any role in the collection, management, analysis, or interpretation of the data; writing of the report; or the decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results
Of the 307 patients who met the entry criteria and were randomly assigned combination therapy (pegylated interferon alfa-2b and lamivudine) or monotherapy (pegylated interferon alfa-2b and placebo), 266 (87%) were included in the final modified intention-to-treat analysis (figure 1). Of the patients excluded from the final analysis, ten (3%) were found to have lost HBeAg before the start of treatment and seven (2%) did not take any study medication and did not return for any follow-up; 24 (8%) recruited by one centre were excluded because the source data could not be verified. These exclusion criteria for analysis were predefined in the study data-analysis plan. Patients excluded from the final analysis were equally distributed among assigned treatment groups.
Fewer interferon-experienced patients were recruited than expected (55 [21%]); therefore, with the total of 266 patients in the modified intention-to-treat population, the study remained more than adequately powered.
The groups of patients in the final analysis were similar in terms of baseline demographics and disease characteristics (table 1).
At the end of treatment (week 52), more patients in the combination-therapy group than in the monotherapy group showed a response as assessed by serum HBeAg loss (57 [44%] vs 40 [29%], p=0·01; table 2). However, this difference was not sustained at the end of follow-up (week 78). At that time, 46 (35%) of the combination-therapy group and 49 (36%) of the monotherapy group had a sustained response.
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Similarly, at the end of treatment, more patients in the combination-therapy group than in the monotherapy group had HBV DNA suppressed to below 200000 copies per mL (96 [74%] vs 40 [29%], p<0·0001; table 2), and again the greater HBV DNA suppression was not sustained during follow-up (41 [32%] vs 37 [27%]; p=0·44). For the outcome undetectable HBV DNA (HBV negativity by PCR), although more patients in the combination-therapy than in the monotherapy group had responded at the end of treatment (43 [33%] vs 13 [10%], p<0·0001), at the end of follow-up there was no difference between the treatment groups (12 [9%] vs nine [7%]; p=0·43). These response patterns were also reflected by longitudinal serum HBV DNA concentrations, which showed greater reduction of viral load in the group assigned combination therapy than in the monotherapy group, followed by a post-treatment rebound of HBV DNA only for those treated with combination therapy (figure 2).
The response assessed by ALT measurements followed a similar pattern to HBV DNA suppression and loss of HBeAg (table 2). At the end of follow-up, there was no difference in response between patients assigned monotherapy and those assigned combination therapy (44 [32%] vs 46 [35%]; p=0·60) despite a difference at the end of treatment. There was no difference in the proportion of patients with HBsAg loss between the treatment groups at the end of treatment or at the end of follow-up (table 2).
Data on the change in histology of the liver from before treatment to the end of therapy were available for 110 patients (biopsies at this time were optional). Fibrosis scores had improved in 17 (33%) of 52 patients assigned combination therapy and 13 (22%) of 58 assigned monotherapy; 15 (29%) and 23 (40%), respectively, showed no change, and 20 (38%) and 22 (38%) had deteriorated (p=0·22 for improvement or no change vs worsening). For inflammatory changes in the liver, there was little difference between the two treatment groups. Improvements were seen at the end of treatment in 25 (48%) patients assigned combination therapy and 31 (53%) patients assigned monotherapy; 22 (42%) and 21 (36%) showed no change, and five (10%) and six (10%) had deteriorated (p=0·57). Our histology results should be interpreted with caution since post-treatment biopsies were optional and selection might have occurred.
Of the 130 patients assigned combination therapy with lamivudine, 14 (11%) patients had the YMDD mutant at the end of treatment. Two (14%) of them had responded to therapy with loss of HBeAg. Seven (50%) of them had been previously treated with lamivudine and had had a mutant from the start of therapy.
There was a significant difference in sustained response rate according to HBV genotype (by univariate analysis, p=0·01). 42 (47%) patients with genotype A and ten (44%) patients with genotype B had lost HBeAg at the end of follow-up, compared with 11 (28%) patients with genotype C and 26 (25%) with genotype D (figure 3). There was no difference in HBeAg loss according to HBV genotype between the two treatment groups.
To assess the independence of genotype as a prognostic factor, we used multivariate analysis. Patients infected with HBV genotype A were more likely to respond to treatment than those with genotype D (odds ratio 2·4 [95% CI 1·3-4·6], p=0·01) or C (3·6 [1·4-8·9], p=0·006). Patients infected with genotype B were slightly but not significantly more likely to respond than those with genotype C (2·2 [0·7-7·0], p=0·18). Other baseline factors that were predictive of response with multivariate analysis were low viral load (1·6 [1·3-1·8], p=0·009), high ALT concentrations (1·1 [1·0-1·2], p=0·02), and absence of previous interferon therapy (2·2 [1·1-4·5], p=0·04).
Overall, the frequencies and severity of adverse events were similar for the treatment groups. For both treatment groups, the side-effect profile was similar to that seen with standard interferons and no new side-effects that could be attributable to pegylated interferon alfa-2b were reported. Common side-effects included flu-like symptoms, headache, fatigue, and local reaction at the injection site (table 3). There were 32 serious adverse events (12% of patients), of which 17 (53%) were probably related to therapy. These adverse events were: hepatitis flare (four), depression (three), severe neutropenia (three), and one case each of psychosis, seizures, pancreatitis, anxiety, dizziness, diarrhoea, and syncope. All serious adverse events were reversible after treatment was stopped.
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