Peginterferon for HBV Therapy: review of studies
"Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon"
"Peginterferon treatment of at least 6 months should be considered as one of the first-line treatment options for HBV infection......Peginterferon is found to be superior to lamivudine monotherapy .....A staggered approach was adopted in the combination group in which patients received 8 weeks of peginterferon-alpha2b, followed by 24 weeks of combination therapy and then 28 weeks of lamivudine alone. The end of treatment and end of follow-up biochemical and virological responses were significantly better in the combination group... combination with more potent anti-viral agents such as entecavir or telbivudine would be interesting...... The prevalence of YMDD mutant at the end of treatment was much lower when patients also received peginterferon.... Coadministration of lamivudine did not result in improvement in viral suppression..... The severe reactivation of hepatitis after cessation of lamivudine therapy continued to be a concern......"
Alimentary Pharmacology & Therapeutics
Volume 22 Issue 6 Page 519 - September 2005
A. Y. HUI*, H. L.-Y. CHAN*, A. Y.-K. CHEUNG+, G. COOKSLEY & J. J.-Y. SUNG*
*Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong;
+Centre for Epidemiology and Biostatistics, School of Public Health, The Chinese University of Hong Kong, Hong Kong;
Discipline of Medicine, University of Queensland Royal Brisbane Hospital, Herston, Australia
Background: Pegylated interferon-alpha has been shown to be more efficacious than conventional interferon in treating chronic hepatitis C. The use of peginterferon in chronic hepatitis B virus infection with positive hepatitis B e antigen has also been tested in a number of trials since 2003.
Aim: To systematically summarize and compare the results of these studies.
Methods: Four studies were identified from PubMed, Medline and reference lists. Data from the trials were extracted and analysed. Where appropriate, combined odds ratio of different trials was calculated. Safety data including serious adverse events and emergence of drug-resistant mutants were recorded.
Three of the four trials contained predominantly Asian patients.
Peginterferon is found to be superior to lamivudine monotherapy and induced sustained biochemical and virological responses in about one-thirds of patients after 12 months of therapy.
Coadministration of lamivudine did not result in improvement in viral suppression.
Peginterferon appears to reduce the emergence of YMDD mutation in the combination treatment groups.
It was well tolerated with serious adverse events reported in <10% of patients in most trials.
Conclusions: Peginterferon-alpha treatment of at least 6 months should be considered as one of the first-line therapeutic options for hepatitis B virus infection.
Chronic hepatitis B virus (HBV) infection is a serious global public health problem. Of the 2 billion people who have been infected, more than 350 million have chronic hepatitis.1
HBV-infected patients with active disease are characterized by positive hepatitis B surface antigen (HBsAg) for at least 6 months and elevated serum transaminase and HBV-DNA levels.2
The aims of treatment of chronic hepatitis B are to sustain viral suppression and disease remission.
Conventional interferon and nucleoside/nucleotide analogues are currently approved first-line treatments of chronic HBV infection.
The end points used to assess treatment effects include biochemical, virological and histological responses.2 These end points are surrogate markers of the clinically important outcome measures, i.e. the development of liver-related complications and death.
Previous studies on natural history revealed that HBV-infected patients with normal alanine transaminase (ALT), low viral load and mild histological disease have lower risk of cirrhosis and hepatocellular carcinoma.3-5 Hepatitis B e antigen (HBeAg)-positive patients who have achieved seroconversion with development of anti-HBe antibody also have improved prognosis.
Interferon-alpha acts mainly as an immunomodulator and enhances the host cell-mediated immune response in clearing the virus.
A meta-analysis of 15 randomized-controlled studies found that with 3-6 months of interferon-alpha treatment, HBeAg loss, undetectable HBV-DNA using hybridization assays and loss of HBsAg can be achieved in 33%, 37% and 8% of patients respectively.6
This was highly significant compared with the corresponding figures in untreated patients of 12%, 17% and 2%. In the long-term, interferon-alpha-treated patients who responded with HBeAg seroconversion had a lower risk of cirrhotic complications and longer survival rate.
Anti-viral agents such as nucleoside and nucleotide analogues are more widely used in Asia because of a milder side-effect profile. At the end of 1-year therapy with lamivudine, up to 18% of patients developed HBeAg seroconversion.7 Although longer treatment resulted in increased HBeAg seroconversion rate, there was also increased incidence of drug-resistant YMDD mutation and viral breakthrough.8 Adefovir, a nucleotide analogue, is effective against the YMDD mutants but causes drug resistance of its own, albeit at a much slower rate.9
Another major unresolved issue with these anti-viral agents is the timing of cessation of therapy, which in a significant proportion of patients is followed by disease relapse or even severe acute reactivation.
Pegylation is a process whereby polyethylene glycol (PEG) is attached to protein molecules. This results in prolongation of in vivo half-life of the protein. Two types of pegylated interferon-alpha are currently available.10 Peginterferon-alpha2b contains covalently linked recombinant interferon-alpha2b and a straight chain molecule of 12 kDa PEG whereas peginterferon-alpha2a is made up of interferon-alpha2a and a 40 kDa branched PEG. Both peginterferons have been shown to be more efficacious than conventional interferon in treating chronic hepatitis C with similar adverse effect profiles and the added advantage of needing only once weekly dosing.11
Treatment of chronic hepatitis B with peginterferons have been reported in five independent studies over past 2 years, four of them on HBeAg-positive patients.12-16 These studies suggest a more promising result using pegylated interferon than conventional interferon or lamivudine. However, there are important differences among these trials in study design, patient populations and treatment regimen. This review summarized their findings and assessed the impact on our management of the disease.
Only studies performed on HBeAg-positive patients were reviewed. All the studies have been published as full articles and were readily identified on PubMed and Medline (from 1966) with the keywords of 'peginterferon' and 'hepatitis B'.12-16 Additional data were obtained from presentations at the annual meetings of the American Association for the Study of Liver Diseases in Boston in 2004 and the European Association for the Study of the Liver in Paris in 2005.17-20 More liberal search on Medline using general terms such as 'interferon', 'viral hepatitis' and 'chronic viral hepatitis' were also performed but this did not yield other studies of interest. Reference lists of the articles found and from recent reviews on management of chronic hepatitis B were also searched but did not identify additional trials.
The articles were studied and the data extracted by a single investigator (AYH). The data include patient demographics, treatment regimens, baseline ALT, HBV-DNA levels and histological stage. Outcome variables, namely rate of HBeAg seroconversion, loss of HBsAg and viral suppression at the end of treatment and 24 weeks post-treatment, were described. Where appropriate, combined odds ratio (OR) of different trials was calculated. The fixed-effect method suggested by DerSimonian and Laird was used to combine the results and the related significance test to assess the heterogeneity.21 The combined result was an average OR weighted according to the standard error of the OR of the trial. Safety data including common and serious adverse events were also collected. In studies that tested combined peginterferon and lamivudine therapy, the incidence of YMDD mutation was recorded.
Table 1. Summary of study design of the four peginterferon trials on HBeAg-positive chronic hepatitis B
The design of these four studies is summarized in Table 1. With the exception of the study by Chan et al.,14 which was a single-centred trial, all were multicentred involving sites in different countries. The earliest one was a phase II trial comparing peginterferon-alpha2a with conventional interferon-alpha.12 The treatment duration was 24 weeks and the end points were assessed at week 48. The duration of treatment of other studies ranged from 48 to 60 weeks and the primary end points were assessed at 24 weeks post-treatment for sustained response.13-17
All four trials contained patients of similar demographics in terms of age and sex distribution. The majority of patients were in their third or fourth decade of age (range: 29-41 years) and there was a male preponderance in all studies. There were however, marked differences in the ethnicity of patient population. The study by Janssen et al.15 differed from the rest with mainly non-Asian subjects and the majority of their subjects belonged to genotypes A and D while the other three trials contained Asian patients with mainly genotypes B and C. Other differences existed between these studies in patients' baseline characteristics. For example, baseline ALT in Janssen et al's.15 study appeared to be higher that those of other studies, which could be related to slightly different inclusion criteria on ALT level. Different HBV-DNA assays were used in these studies and thus the HBV-DNA levels may not be directly comparable between studies.
In the phase II study, Cooksley et al. showed that peginterferon-alpha2a at 90 mug or 180 mug weekly was better than conventional interferonalpha2a (4.5 MIU thrice weekly) in treatment-naive patients in combined response of HBeAg loss, HBV-DNA suppression (<5 x 105 copies/mL) and ALT normalization (Table 2).12 Combined response was observed in 27% of peginterferon-treated patients and 11% of patients who received conventional interferon. In terms of genotypes of HBV, patients with genotype B responded significantly better than those with genotype C. Nevertheless, it should be noted that the study found no difference between conventional interferon and peginterferon when individual efficacy outcomes were compared. Furthermore, the dosage of conventional interferon used in the study was lower than that used in some countries which is 5 MIU daily or 10 MIU thrice weekly2, 22 although it was the dose commonly used in Asia as it had been shown to be as effective as the higher dose.23
ALT, alanine transaminase; ULN, upper limit of normal; HBeAg, Hepatitis B e antigen; HBV, hepatitis B virus.
In the trial by Lau et al.,16-18 significantly more patients in the peginterferon-containing arms had sustained biochemical and virological responses irrespective of whether the patients had or had not previously received anti-HBV therapy. The superior efficacy of peginterferon was present even with subgroup analysis based on baseline ALT levels. In general patients with lower ALT had lower rate of virological response. Among those with baseline ALT <2 x upper limit of normal (ULN) and who received peginterferon-alpha2a monotherapy, the rate of sustained virological response was 29%; in contrast, patients with ALT >5 x ULN had a response rate of 41%. The corresponding figures for patients who received lamivudine monotherapy were 20% and 28% respectively. Meanwhile, patients with genotype C HBV infection appeared to respond equally well to peginterferon as genotype B patients.16, 19
Two studies on HBeAg-positive patients used peginterferon-alpha2b. As well as differences in ethnic background of patients and genotypes of HBV, the two studies also differed in patients' treatment history and study design. Chan et al.14 recruited treatment-naive patients only and compared lamivudine monotherapy (100 mg daily for 52 weeks) and combined peginterferon-alpha2b and lamivudine treatment. A staggered approach was adopted in the combination group in which patients received 8 weeks of peginterferon-alpha2b, followed by 24 weeks of combination therapy and then 28 weeks of lamivudine alone. The end of treatment and end of follow-up biochemical and virological responses were significantly better in the combination group (Figure 1).
Figure 1. End of follow-up responses in ALT normalization, hepatitis B e antigen (HBeAg) seroconversion and hepatitis B virus (HBV)-DNA suppression of the four trials. cIFN, conventional interferon monotherapy; pIFN, peginterferon monotherapy; Lam, lamivudine monotherapy; Comb, combined peginterferon and lamivudine; ALT, alanine transaminase. * Statistically significant compared with lamivudine monotherapy.
In Janssen et al's.15 study, 12% of 266 predominantly Caucasian patients from 15 countries had previously failed lamivudine treatment and 21% failed conventional interferon. The dose of peginterferon-alpha2b was weight-adjusted for patients of body weight 55 kg or less. Patients of weight over 55 kg received 100 mug weekly for 32 weeks and 50 mug weekly between weeks 32 and 52. Although the end of treatment biochemical response and HBV-DNA suppression were significantly better in the combination group, there was no difference between the two groups in all efficacy measures at the end of follow-up. The predictors of response included high ALT, low viral load and absence of previous interferon treatment. Patients with genotype A infection had the best sustained response rate (47%) which was significantly better than that of genotype D (25%). In both peginterferon-alpha2b trials, no difference in histological response was seen between treatment groups.
In the study by Janssen et al's.,15 the end of treatment biochemical response was only 51% in the combination therapy group whilst the corresponding figure was 90% in Chan et al.14 This was surprising because lamivudine alone has been shown to effectively normalize ALT in the majority of patients during the first year of treatment.7 Furthermore, 7% of patients in each group in Janssen et al's.15 trial lost HBsAg. A much lower rate of HBsAg loss was noted in the other studies. This could have been explained by the fact that Janssen et al.15 recruited predominantly European patients and 34% of them had genotype A infection. In the latest combined analysis of the two peginterferon-alpha2a trials by Lau et al. and Marcellin et al.13 (on HBeAg-negative patients), 61% of all sustained HBsAg seroconversion occurred in genotype A-infected patients.20
Despite the differences in types of peginterferon, patient population, HBV genotype and treatment regimen, the four trials on HBeAg-positive patients individually and together appear to demonstrate that peginterferon is superior to lamivudine and probably conventional interferon monotherapy in inducing sustained biochemical and virological response. Coadministration of lamivudine caused more pronounced on-treatment viral suppression but this was not sustained after cessation of therapy. In total, 51, 453, 322 and 451 patients received conventional interferon, peginterferon monotherapy, lamivudine monotherapy or combined treatment respectively. Sustained ALT normalization was achieved in 25, 38, 28 and 39% respectively. The corresponding figures for sustained HBeAg seroconversion were 25, 31, 18 and 29% and for sustained viral suppression (<5 x 105 copies/mL) were 25, 31, 21 and 34%.
Analysis of combined data from Lau et al. and Chan et al's.14 studies were performed to compare the effect of lamivudine monotherapy vs. combined peginterferon and lamivudine therapy. The combined OR was 1.751 [95% confidence interval (CI): 1.260-2.435] for end of follow-up ALT normalization, 1.760 (95% CI: 1.214-2.552) for HBeAg seroconversion and 1.983 (95% CI: 1.391-2.825) for HBV-DNA suppression. The results confirmed the inferiority of lamivudine monotherapy. Similar analysis was performed on data from Lau et al. and Janssen et al's.15 studies to compare the effect of peginterferon monotherapy vs. combined lamivudine and peginterferon therapy (Figure 3). No difference in treatment effect was demonstrated, as in individual trials.
Tolerability and safety of peginterferon
The rate of dose modification varied greatly between trials (Table 4). The common causes of dose modification were laboratory abnormality such as raised ALT and neutropenia, and adverse events. The most frequently reported adverse events in peginterferon-treated patients were those normally associated with conventional interferon.12 These included pyrexia, myalgia, fatigue, headache and so on. Despite presence of these adverse effects, rate of withdrawal from peginterferon treatment was lower than 10% in all trials. Serious adverse events, albeit uncommon, were noted in between 4 and 7% of patients treated with peginterferon-alpha2a and between 8 and 12% of patients treated with peginterferon-alpha2b. The most common serious adverse events were infection, thyroid disorder, depression and hepatitis flare. There was no death associated with the treatment, or liver decompensation.
It is well known that lamivudine monotherapy for a prolonged period causes the emergence of drug-resistant mutant. The prevalence of YMDD mutant at the end of treatment was much lower when patients also received peginterferon. The severe reactivation of hepatitis after cessation of lamivudine therapy continued to be a concern. Lau et al.16 reported two cases of hepatic decompensation secondary to postlamivudine relapse. One of the patients needed liver transplantation while the other one succumbed.
Despite variations in study design among the four studies, the results were consistent. Peginterferon alone for 6-12 months achieved a sustained virological response in about one-thirds of patients treated. Patients including those with compensated cirrhosis appeared to tolerate peginterferon well despite the need for dose modification in some. Serious adverse events related to peginterferon did occur but none appeared to be life-threatening. Interferon treatment for HBV infection carries the inherent advantages of a finite duration of therapy and little concern of drug resistance. With the additional benefit of once weekly dosing in its pegylated form and the results from these studies suggesting superior efficacy compared with conventional interferon or lamivudine, peginterferon may indeed give new hope to patients with HBV infection.
While the results of the four trials were promising, there are questions that remain unresolved. Is peginterferon really more efficacious than conventional interferon which has been shown to have a response rate about 33% in a meta-analysis?6 Cooksley's study has been the only trial to date directly comparing efficacy of the two.10 It may not have adequately answered this question due to the dosage of conventional interferon used and the small sample size. The remaining three peginterferon trials treated patients for approximately 1 year in contrast to most studies on conventional interferon which had much shorter treatment durations of 16-24 weeks. A new and larger study comparing the two preparations of interferon in HBV-infected patients would be needed. On the contrary, the optimal duration of therapy is still unclear. Cooksley et al. treated patients for 6 months but the sustained response rate in their study was on par with the other three HBeAg-positive trials. Nevertheless, Lau et al.17 demonstrated in their study a progressive increase in cumulative HBeAg seroconversion during treatment and follow-up periods. It is currently not clear whether a treatment period longer than 12 months can achieve an even higher rate of sustained response. Meanwhile, on-treatment biochemical or virological parameters may help decide when therapy should be stopped. It has been suggested that in HBeAg-positive patients, treatment with nucleoside/nucleotide analogues could be stopped after a minimum of 1 year and 3-6 months after HBeAg seroconversion.24 Further research is needed to determine if there is a threshold of serum HBV-DNA level that could reliably predict sustained response. Such work will hopefully be facilitated by the use of standardized unit of HBV-DNA that would allow cross-comparison of different assays and studies.
Predictors of response to conventional interferon or nucleoside analogue include high baseline ALT and low HBV-DNA levels.2 More research is needed to determine if the same applies to peginterferon. Lessons can also be learnt from treatment of chronic hepatitis C and it is worthwhile to investigate if early viral suppression is indicative of ultimate sustained response or vice verse.11 In this respect, careful study of the viral kinetics in future trials is needed to allow us to differentiate the responders from the non-responders based on the early viral response. Another possible viral determinant of response is the HBV genotype. Future studies specifically designed and powered to address this issue will be needed. Lastly, new research technique also means that it is now feasible to quantify intrahepatic cccDNA, which may conceivably and more accurately predict the sustained response rate.25
The studies thus far suggest that coadministration of lamivudine to peginterferon did not confer additional benefit. This is disappointing as there is theoretical advantage and synergy in using an immunomodulator and an anti-viral agent together. The former may enhance immune clearance of HBV-infected hepatocytes while the latter stops viral replication, thereby increasing the chance of successful elimination of HBV. In three of these studies, peginterferon and lamivudine were commenced simultaneously and the combination group had similar response rate to peginterferon monotherapy group. In the study by Chan et al.,14 combination treatment was given in a staggered manner but there was no peginterferon monotherapy group. The argument for giving peginterferon first is that after the initial enhanced immune clearance of intrahepatic HBV including cccDNA, the stage is set for addition of lamivudine to halt viral replication and prevent reinfection of hepatocytes. The opposite approach is to give anti-viral treatment first. The theoretical advantage is that by lowering the viral load, anti-viral agent may improve the response rate to subsequent interferon treatment. The case could also be made for patients with very high ALT (>10 x ULN) to receive lamivudine first before adding peginterferon because the latter could potentially induce hepatic flare and in such patients may lead to decompensation. Undoubtedly new trials comparing different ways of combining peginterferon with anti-viral agents accompanied by detailed viral kinetics study is needed. Furthermore, combination with more potent anti-viral agents such as entecavir or telbivudine would be interesting.
An interesting finding from these studies is that incidence of YMDD mutation is reduced in patients treated with combination therapy, compared with those receiving lamivudine monotherapy. It is uncertain whether this was a direct consequence of more effective on-treatment viral suppression or a result of immunomodulation by peginterferon. The finding however, raises the possibility of introducing peginterferon to patients on long-term anti-viral treatment as a measure of lowering the chance of emergence of drug resistance. Alternatively, adding peginterferon to anti-viral agent in patients already harbouring drug-resistant mutant may help suppress the virus.
Another unresolved issue is related to the histological response to peginterferon therapy in HBV infection. The studies so far have provided no evidence of efficacy in terms of histological improvement associated with biochemical or virological response. Meanwhile, longer follow-up of patients will be needed to detect delayed viral clearance or relapse, i.e. durability of response. More importantly, the clinical outcomes in terms of liver-related complications, mortality and hepatocellular carcinoma should be assessed. Besides, are the two types of peginterferon equipotent? Peginterferon-alpha2b has a shorter half-life than peginterferon-alpha2a26 but the studies thus far have shown fairly consistent efficacy and safety profile of the two peginterferons. However, because of the heterogeneity of these trials, comparison of the two drugs is not possible. A study with head-to-head comparison of the two agents will be needed to resolve the issue.
In conclusion, the latest trials support the notion that peginterferon is an effective and safe treatment of chronic hepatitis B. Addition of lamivudine does not appear to improve the efficacy. Peginterferon treatment of at least 6 months should be considered as one of the first-line treatment options for HBV infection.