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48 weeks pegylated interferon alpha-2a is superior to 24 weeks of pegylated interferon alpha-2b in achieving hepatitis B e antigen seroconversion in chronic hepatitis B infection
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Alimentary Pharmacology & Therapeutics
Volume 23 Page 1171 - April 2006
C.-K. HUI*, , , L. S. W. LAI , P. LAM , H.-Y. ZHANG*, , T.-T. FUNG**, S.-T. LAI , W.-M. WONG , C.-M. LO , , S.-T. FAN , , N. LEUNG & G. K. K. LAU*, , FOR THE HONG KONG LIVER FIBROSIS STUDY GROUP
*Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China; Centre For The Study of Liver Disease, The University of Hong Kong, Hong Kong SAR, China; Research Centre for Infection and Immunity, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, Caritas Medical Centre, Hong Kong SAR, China; Department of Pathology, Queen Elizabeth Hospital, The University of Hong Kong, Hong Kong SAR, China; **Department of Medicine, Kwong Wah Hospital, Hong Kong SAR, China; Department of Medicine, Princess Margaret Hospital, Hong Kong SAR, China; St Paul's Hospital, Hong Kong SAR, China; Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China
....the current licensed duration of therapy with conventional interferon alpha is 16-24 weeks. At the moment, there is no data on whether 24 weeks of pegylated interferon alpha is adequate for the treatment of chronic HBV infection. We have, therefore, undertaken this retrospective review of HBeAg positive Chinese patients treated with 48 weeks of pegylated interferon alpha-2a or 24 weeks of pegylated interferon alpha-2b in Hong Kong.... On logistic regression analysis, only 48 weeks treatment with pegylated interferon alpha-2a was independently associated with an increased rate of SVR... At the end of follow-up, 10 of the 29 patients (34.5%) treated with 48 weeks of pegylated interferon alpha-2a compared with two of the 24 patients (8.3%) treated with 24 weeks of pegylated interferon alpha-2b had developed SVR (P = 0.04)... It may be possible that, like conventional interferon, extending the treatment duration of pegylated interferons can increase the rate of HBeAg seroconversion.... At the end of follow-up, seven of the 29 patients (24.1%) treated with 48 weeks of pegylated interferon alpha-2a compared with four of the 24 patients (16.7%) treated with pegylated interferon alpha-2b had HBV DNA <105 copies/mL (P = 0.74)...
Figure 1. Rates of (a) Hepatitis B e Antigen seroconversion
Summary
Background/aim: Although 48-week therapy with pegylated-interferons has been shown to be effective for the treatment of chronic hepatitis B virus infection, the efficacy of a shorter duration of therapy with pegylated interferons is unknown.
Method: We reviewed 53 hepatitis B e antigen positive Chinese patients treated with 48 weeks of pegylated interferon alpha-2a or 24 weeks of pegylated interferon alpha-2b. Sustained virological response was defined as hepatitis B e antigen seroconversion and hepatitis B virus DNA <105 copies/mL (100,000) at week 72.
Results:
Twenty-nine patients were treated with 48 weeks of pegylated-interferon-alpha-2a and 24 patients with 24 weeks of pegylated-interferon-alpha-2b.
At the end-of-therapy, hepatitis B e antigen seroconversion and hepatitis B virus DNA <105 copies/mL were similar between the two groups of patients [9/29 (31.0%) vs. 2/24 (8.3%), respectively, P = 0.09].
At week 72, 10 of the 29 patients (34.5%) treated with 48 weeks of pegylated-interferon-alpha-2a compared with two of the 24 patients (8.3%) treated with 24 weeks of pegylated-interferon-alpha-2b had sustained virological response (P = 0.04). By logistic analysis, 48 weeks of pegylated-interferon-alpha-2a was independently associated with sustained virological response (P = 0.04 adjusted hazards-ratio 9.37).
Conclusion Further studies are required to determine the optimal duration of therapy with pegylated interferons in chronic hepatitis B.
Introduction
Hepatitis B virus (HBV) infection is one of the commonest viral infection in the world. Approximately 2 billion people have been infected with HBV and 350 million of them remain chronically infected. Around 25-40% will eventually die of liver disease (viz. cirrhosis with or without hepatocellular carcinoma); the death rate being 50% for males and 15% for females.1 Conventional interferon alpha-2b is the first drug to be approved by the US Food and Drug Administration (FDA) for treatment of chronic HBV infection followed by lamivudine, adefovir, entecavir and most recently pegylated interferon alpha-2a.
Conventional interferon alpha treatment at a dose of 3-10 MIU for 4-6 months results in a loss of hepatitis B e antigen (HBeAg) in 33% of mainly Caucasian patients.2 However, conventional interferon alpha needs to be administered subcutaneously daily or three times a week and is associated with more peak-trough related side-effect events.2 Pegylated interferon alpha-2a and pegylated intereron alpha-2b are a group of therapeutic agents that are pegylated by incorporation of a polyethylene moiety into the active product. Pegylation of the interferon alpha molecule is undertaken to enhance the pharmacokinetic properties of unmodified interferon alpha, enabling once a week dosing.
Recently, in a large multinational study conducted mainly in Asia-Pacific countries, 814 HBeAg positive chronic HBV infected patients were randomized to receive either pegylated interferon alpha-2a 180 ƒÊg weekly monotherapy, pegylated interferon alpha-2a 180 ƒÊg weekly plus lamivudine 100 mg daily combination therapy or lamivudine 100 mg daily for a total of 48 weeks and assessed at 24 weeks after the end of therapy.3 The use of pegylated interferon alpha-2a as monotherapy or in combination with lamivudine for 48 weeks resulted in superior HBeAg seroconversion when compared with lamivudine monotherapy alone.3
Another study comparing the efficacy of combination pegylated interferon alpha-2b plus lamivudine vs. pegylated interferon alpha-2b monotherapy has been performed in HBeAg positive patients. In this study, the addition of lamivudine to pegylated interferon alpha-2b did not increase the rate of HBeAg seroconversion when compared with pegylated interferon alpha-2b monotherapy alone.4 As 48-week therapy with lamivudine has been licensed for the treatment of chronic HBV by the FDA, both these studies on HBeAg positive patients utilized the same duration of pegylated interferon alpha in order to enable direct comparison of the efficacy of pegylated interferon alpha with lamivudine.
On the other hand, the current licensed duration of therapy with conventional interferon alpha is 16-24 weeks. At the moment, there is no data on whether 24 weeks of pegylated interferon alpha is adequate for the treatment of chronic HBV infection. We have, therefore, undertaken this retrospective review of HBeAg positive Chinese patients treated with 48 weeks of pegylated interferon alpha-2a or 24 weeks of pegylated interferon alpha-2b in Hong Kong.
RESULTS
During this period, there were 149 HBeAg positive patients with serum ALT levels above the upper limit of normal; 84 patients were treated with lamivudine (16 were part of the phase III pegylated interferon alpha-2a study);3 30 patients were recruited into adefovir dipivoxil monotherapy vs. adefovir dipivoxil plus emtricitabine combination phase II study;9 12 patients were treated with combination pegylated interferon alpha-2a plus lamivudine as part of the pegylated interferon alpha-2a phase III study3 while another 23 patients refused treatment.
Altogether, 24 patients were treated with 24 weeks of pegylated interferon alpha-2b from 2001 to 2003 while 29 patients were treated with 48 weeks of pegylated interferon alpha-2a from 2002 to 2004 (16 of these patients were treated as part of the phase III pegylated interferon alpha-2a study3). The baseline demographics of these patients are shown in Table 1. There was no significant difference in the baseline demographics between the two groups of patients. Although insignificant, there was a higher number of patients with serum ALT levels more than 200 U/L among those treated with 48 weeks of pegylated interferon alpha-2a. No patients received either 24 weeks of pegylated interferon alpha-2a or 48 weeks of pegylated interferon alpha-2b during the same period.
HBeAg seroconversion and HBV DNA <105 copies/mL
All patients completed the end of follow-up. At the end of treatment, virological response occurred in nine of the 29 patients (31.0%) treated with 48 weeks of pegylated interferon alpha-2a compared with two of the 24 patients (8.3%) treated 24 weeks of pegylated interferon alpha-2b (P = 0.09) (Figure 1a). At the end of follow-up, 10 of the 29 patients (34.5%) treated with 48 weeks of pegylated interferon alpha-2a compared with two of the 24 patients (8.3%) treated with 24 weeks of pegylated interferon alpha-2b had developed SVR (P = 0.04) (Figure 1a).
At week 24 of therapy (week 24 in the 48-week pegylated interferon alpha-2a group and the end of therapy in the 24-week pegylated interferon alpha-2b group), four of the 29 patients (13.8%) treated with 48 weeks of pegylated interferon alpha-2a compared with two of the 24 patients (8.3%) treated with pegylated interferon alpha-2b had HBeAg seroconversion and HBV DNA <105 copies/mL (P = 0.68) (Figure 1a).
Suppression of HBV DNA <105 copies/mL
At the end of therapy, HBV DNA was <105 copies/mL in 20 of the 29 patients (69.0%) treated with 48 weeks of pegylated interferon alpha-2a compared with 14 of the 24 patients (58.3%) treated with 24 weeks of pegylated interferon alpha-2b (P = 0.42) (Figure 1b). At the end of follow-up, seven of the 29 patients (24.1%) treated with 48 weeks of pegylated interferon alpha-2a compared with four of the 24 patients (16.7%) treated with pegylated interferon alpha-2b had HBV DNA <105 copies/mL (P = 0.74) (Figure 1b).
When the two groups were compared at week 24 of therapy (week 24 in the 48-week pegylated interferon alpha-2a group and end of therapy in 24-week pegylated interferon alpha-2b group), HBV DNA was <105 copies/mL in 15 of the 29 patients (51.7%) treated with 48 weeks of pegylated interferon alpha-2a compared with 14 of the 24 patients (58.3%) treated with pegylated interferon alpha-2b (P = 0.78) (Figure 1b).
Normalization of serum ALT
At the end of therapy, eight of the 29 patients (27.6%) treated with 48 weeks of pegylated interferon alpha-2a had normalization of serum ALT compared with 10 of the 24 patients (41.7%) treated with 24 weeks of pegylated interferon alpha-2b (P = 0.28). At the end of follow-up, normalization of serum ALT occurred in 10 of the 19 patients (34.5%) treated with 48 weeks of pegylated interferon alpha-2a compared with 14 of the 24 patients (58.3%) treated with 24 weeks of pegylated interferon alpha-2b (P = 0.08).
Safety results
None of the patients in both groups had withdrawal from therapy (P = NS). There was no difference in the need for dose modifications or adverse events between the two groups of patients (all P = NS) (Table 2).
Factors associated with sustained virological response
On logistic regression analysis, only 48 weeks treatment with pegylated interferon alpha-2a was independently associated with an increased rate of SVR (Table 3).
Table 3. Univariate and multivariate regression analysis showing factors associated with SVR
Discussion
Conventional interferon alpha has suboptimal pharmacokinetics, resulting in an inconvenient dosing schedule and fluctuating drug exposure. Pegylated interferon alpha-2a, a 40 kDa branched pegylated chain linked to interferon alpha-2a, and pegylated interferon alpha-2b, derived from interferon alpha-2b consisting of a linear 12 kDa polyethylene glycol, both have better pharmacokinetics than conventional interferon alpha.1012 The study on the efficacy and safety of pegylated interferon alpha-2a published in 2003 was the first report on the use of pegylated interferon in the treatment of chronic HBV infection.13 In this phase II study, 6 months therapy with pegylated interferon alpha-2a resulted in a significantly higher response rate when compared with conventional interferon alpha-2a.13
This result led to two phase III studies on the use of pegylated interferon alpha-2a on chronic HBV. However, these phase III trials on pegylated interferon alpha-2a used 48-week of therapy duration to facilitate direct comparison with the efficacy of lamivudine, the first nucleoside analogue licensed for the treatment of chronic HBV by the FDA.3, 1416 Studies on pegylated interferon alpha-2b in Caucasians also used a 48 week treatment duration while another study on pegylated interferon alpha-2b in Chinese HBeAg positive chronic HBV patients used a 32 week treatment duration.4, 17
Although, these four studies demonstrated the efficacy of pegylated interferons either as monotherapy or in combination with lamivudine for the treatment of HBeAg positive and negative chronic HBV infection,3, 4, 16, 17 it is uncertain if a different duration of treatment with pegylated interferons will affect the SVR rate. We have, therefore, performed a retrospective review of our experience in treating Chinese HBeAg positive patients with 48 or 24 weeks of pegylated interferons in Hong Kong. However, the difference between the two types of pegylated interferons, the retrospective design and lack of randomization are the major limitations of the current study. Furthermore, the use of two different pegylated interferons sequentially at different time period may also have introduced a bias.18
Patients were treated with pegylated interferon alpha-2b as it was demonstrated to be superior to conventional interferon alpha for the therapy of chronic HCV at the time.19, 20 The 24-week treatment period was based on the period of therapy approved by the FDA for conventional interferon alpha.2 As data on the superior efficacy of treating chronic HBV with 48 weeks of pegylated interferon alpha-2a began to emerge, we began to treat patients with 48 weeks of pegylated interferon alpha-2a.3, 16
Despite these limitations, one interesting hypothesis that can be generated from this study is that a 48-week therapy with pegylated interferon alpha-2a may be superior to 24 weeks of pegylated interferon alpha-2b. It may be possible that, like conventional interferon, extending the treatment duration of pegylated interferons can increase the rate of HBeAg seroconversion.21 In that particular study, Janssen et al. found that prolonging the duration of conventional interferon alpha from 16 to 32 weeks increased HBeAg seroconversion from 12% to 28%.21
Here, 48 weeks of pegylated interferon alpha-2a resulted in a SVR of 34.5% at the end of follow-up when compared with the 8.3% achieved with 24 weeks of pegylated interferon alpha-2b. There was also a trend towards a higher virological response at the end of therapy with a 48-week course of pegylated interferon alpha-2a when compared with a 24-week course of pegylated interferon alpha-2b. Furthermore, there was no difference in the HBeAg seroconversion rate or suppression of HBV DNA to <105 copies/mL when the two groups were compared at week 24 (week 24 for the group of patients treated with 48 weeks of pegylated interferon alpha-2a and the end of therapy for the group of patients treated with 24 weeks of pegylated interferon alpha-2b).
The increase in SVR with 48 weeks of pegylated interferon alpha-2a does not seem to be associated with a higher HBV DNA suppression (Figure 1b). This is similar to the findings from the two pegylated interferons studies, that better HBV DNA suppression with combination pegylated interferon plus lamivudine did not translate into an increase in HBeAg seroconversion.3, 4 This is in keeping with the recent observation that more profound viral suppression achieved with entecavir, the most potent nucleoside/nucleotide analogue available, or with combination lamivudine plus telbivudine also did not translate into a higher HBeAg seroconversion.22, 23
In our locality where HBV infection is endemic, the most common mean of infection is by vertical transmission, from chronically infected mother to baby.24 This would suggest that the majority of the patients in this review had acquired the infection during the neonatal period. Thus, these patients have been infected for over three decades before they were treated with pegylated interferons. Thus, 24 weeks therapy with pegylated interferons may be inadequate for the therapeutic restoration of the HBV specific immune system, explaining for the lower SVR when compared with 48 weeks of pegylated interferon alpha-2a.25 Therefore, there is a need to conduct a large scale prospective randomized study with different durations of the same pegylated interferon to determine if a longer duration of treatment with pegylated interferon alpha can improve SVR in HBeAg positive Chinese patients.
One other possible explanation for the observed difference may be that pegylated interferon alpha-2a has better efficacy than pegylated interferon alpha-2b in Chinese patients. However, previous studies with conventional interferon alpha-2a and conventional interferon alpha-2b did not demonstrate a difference in the efficacy of these two drugs in Chinese HBeAg positive patients.26, 27 Additionally, the small sample size in this review when compared with the phase III study3 and, the higher number of patients with serum ALT more than 200 U/L in the pegylated interferon alpha-2a group (Table 1) may have also introduced a type II error and the observed difference may have occurred by chance.3
In conclusion, the optimal duration of therapy with pegylated interferons for chronic hepatitis B in Chinese patients is still uncertain. More studies are needed to determine the optimum duration of therapy with pegylated interferons alpha.
Patients and methods
We have retrospectively reviewed our experience in treating chronic HBV infected HBeAg positive Chinese patients treated with pegylated interferon alpha at the Liver Clinic of the Queen Mary Hospital, Caritas Medical Centre, Kwong Wah Hospital and Alice Ho Miu Ling Nethersole Hospital from 2001 to 2004. Consecutive patients were included into this review if they fulfilled the following criteria: (i) hepatitis B surface antigen (HBsAg) positive for at least 6 months; (ii) HBeAg positive for at least 6 months; (iii) elevation of serum alanine aminotransaminase (ALT) level above the upper limit of normal (normal range: 13-31 U/L for females and 13-53 U/L for males) for at least 6 months before commencement of therapy; and (iv) treated with pegylated interferon alpha-2b (Schering-Plough, Kenilworth, NJ, USA) 1.5 ƒÊg/kg weekly for 24 weeks or pegylated interferon alpha-2a (Roche, Basel, Switzerland) 180 ƒÊg weekly for 48 weeks. Patients were excluded from the review if they had: (i) previous nucleoside or nucleotide analogue therapy; (ii) been treated with immunomodulators in the 24 weeks prior to commencement of pegylated interferon alpha; (iii) normal serum ALT level at the start of pegylated interferon alpha; (iv) decompensated liver disease; (v) co-existing psychiatric disease; (vi) neutrophil count of <1500 mm3; (vii) platelet count of <90 000 mm3 or (viii) co-infection with either hepatitis C virus (HCV), human immunodeficiency virus or hepatitis D virus.
Hepatitis B surface antigen, HBeAg, hepatitis B e antibody (anti-HBe) [Abbott Laboratories, North Chicago, IL, USA] and anti-HCV (Ortho Diagnostics System, Raritan, NJ, USA) were assayed with the second-generation enzyme-linked immunosorbent assay. HBV genotype was determined according to the methods previously described.5 All patients underwent a physical examination and blood testing for liver biochemistry [ALT, aspartate aminotransaminase, alkaline phosphatase, gamma-glutamyl transpeptidase, albumin and bilirubin], complete blood count, prothrombin time, activated partial thromboplastin time and renal biochemistry before commencement of therapy. A pre-treatment liver biopsy was performed before commencement of pegylated interferon alpha. The liver biopsy was scored for necroinflammation by using the modified Knodell histologic activity index scoring system (score range 0-18) and liver fibrosis by using the Ishak scoring system (score range 0-6).6
All patients were followed-up every 8 weeks until week 72 (end of follow-up). Liver biochemistry, complete blood count, thyroid function test, HBsAg, HBeAg and anti-HBe were checked at each follow-up. HBV DNA was checked with an in-house real time PCR assay, according to the methods previously described, before commencement of therapy, at the end of therapy and at 24 weeks after completion of therapy.7, 8 The sensitivity of this HBV DNA assay was 100 copies/mL with a linear range of 100 to 108 copies/mL.7, 8
Definition of endpoints
Virological response, assessed at the end of therapy, was defined as HBeAg seroconversion and suppression of HBV DNA to <105 copies/mL. Sustained virological response (SVR), assessed at the end of follow-up (week 72), was defined as HBeAg seroconversion and suppression of HBV DNA to <105 copies/mL. HBeAg seroconversion was defined as loss of HBeAg with the development of anti-HBe for three consecutive readings 8 weeks apart.
Statistical analysis
All statistical analyses were performed using the Statistical Program for Social Sciences (SPSS 10.0 for windows; SPSS Inc., Chicago, IL, USA). The Mann-Whitney U-test was used for continuous variables with skewed distribution and the chi-squared with Yates' correction for continuity or Fisher's exact test for categorical variables. The primary endpoint was SVR. A secondary analysis was performed to identify factors that were associated with SVR at the end of follow-up. Factors that were significant in the univariate analysis were subsequently incorporated into a logistic regression analysis to identify the most important factors associated with SVR at the end of follow-up. All statistics were performed on the intention-to-treat population. Statistical significance was defined as P < 0.05.
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