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Genotype B and Younger Patient Age Associated with Better Response to Low-Dose Therapy: A Trial with Pegylated/Nonpegylated Interferon-α-2b for Hepatitis B e Antigen—Positive Patients with Chronic Hepatitis B in China

  1. Hong Zhao1,
  2. Fuat Kurbanov7,
  3. Mo-Bin Wan3,
  4. You-Kuan Yin4,
  5. Jun-Qi Niu5,
  6. Jin-Lin Hou6,
  7. Lai Wei2,
  8. Gui-Qiang Wang1,
  9. Yasuhito Tanaka7,
  10. Masashi Mizokami7, and
  11. Chong-Wen Si1
  1. 1Peking University First Hospital, Beijing
  2. 2People's Hospital, Peking University, Beijing
  3. 3Changhai Hospital, Second Military University, Beijing
  4. 4Huashan Hospital, Fudan University, Shanghai
  5. 5First Hospital, Jilin University, Changchun, Jilin
  6. 6Nanfang Hospital, First Military University, Guangzhou, China
  7. 7Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  1. Reprints or correspondence: Dr. Chong-Wen Si, Dept. of Infectious Diseases, Peking University First Hospital, 8, Xishiku St., West District, Beijing 100034, China (sichongwenbd{at}sina.com).
 
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Abstract

Background. Cost and clinically significant adverse effects are the major limiting factors of interferon (IFN) use in therapy for chronic hepatitis B virus (HBV) infection. A clinical trial was conducted in China to study the efficiency and clinical relevance of low-dose regimen of IFN treatment for chronic HBV infection and to reveal factors predicting sustained combined response.

Methods. During a randomized, open-label control study, hepatitis B e antigen (HBeAg)–positive patients with chronic HBV infection (n = 230) were assigned to receive pegylated IFN-α-2b (1.0 µg/kg) (n = 115) or IFN-α-2b (3 MIU; n = 115) for a 24-week period. Sustained combined response was assessed 24 weeks after the completion of treatment.

Results. The greater rate of HBeAg loss in the pegylated IFN-group (23%) was the only statistically significant difference between the 2 treatment arms observed at the end of follow-up. The results of the multivariate statistical analysis revealed that HBV genotype B and patient age (≤25 years) were 2 independent factors associated with sustained combined response. A total of 40% of patients with HBV genotype B aged ≤25-years achieved sustained combined response. Only 4 (1.7%) of 230 patients discontinued therapy because of clinically significant adverse effects.

Conclusions. The choice of low-dose IFN regimen might be a relevant clinical option to reduce the cost and adverse effects of therapy for younger patients with chronic HBV infection and genotype B infection in countries where it is prevalent.

More than 350 million people in the world are at risk of developing liver cirrhosis and hepatocellular carcinoma and of dying of chronic hepatitis B virus (HBV) infection if not provided with the appropriate treatment [1, 2]. Virological (HBV-DNA suppression), serological (hepatitis B e antigen [HBeAg] loss and seroconversion and hepatitis B surface antigen [HBsAg] loss and seroconversion), biochemical (alanine aminotransferase [ALT] level normalization), and clinical (reduction of liver damage) end points are used to assess treatment efficacy [3]. Two different strategies are currently available for management of chronic HBV infection: finite curative (using IFNs) and indefinite suppressive treatment, which uses direct antiviral agents, such as nucleos(t)ide analogues. Currently approved drugs include conventional IFN, pegylated IFN, lamivudine, and adefovir dipivoxil; however, each of these has disparate benefits and risks; lamivudine therapy is associated with high rates of viral resistance, but IFN-α-2b therapy has an effect of lower resistance. Adefovir therapy is associated with a lower risk of clinically significant adverse effects and viral resistance; however, the improved therapeutic benefits may offset its increased cost when compared with either IFN or lamivudine used as a monotherapy [3, 4]. Thus, studies have shown that for patients with chronic HBV infection with elevated ALT levels, monotherapy with IFN, but not lamivudine or adefovir, was most cost effective [4]. Newer agents that exhibit increased potency and favorable toxicity profiles have been approved or are being evaluated in clinical trials. The most recently approved of these new therapies is entecavir, which has been shown to be optimal for nucleos(t)ide analogue—naive persons (R.G. Gish, personal communication) [5].

The responses to antiviral therapy are invariably influenced by both host and viral factors. HBV has been classified into 8 genotypes (A—H) according to the genome sequence divergence [6]. Previous reports showed that the HBeAg-loss rate induced by pegylated IFN-α-2b varied by HBV genotypes (P < .01), as follows: A, 42 patients (47%); B, 10 patients (44%); C, 11 patients (28%); and D, 26 patients (25%) [7]. Genotypes B and C are the most prevalent genotypes in individuals native to Asian countries, including those in China, which has the largest pool of HBV-infected individuals in the world [8, 9].

To our knowledge, there have been no clinical data revealing the efficiency and clinically significant adverse effects of the lower-dose IFN-α-2b regimen in the context of comparative analyses of the drug formation (pegylated vs. nonpegylated) in patients with different genotypes (B vs. C). In our randomized, open-label control study of pegylated versus nonpegylated IFN-α-2b, we assessed virologic and patient factors that are predictive of sustained combined response and that might be useful when the most clinically beneficial and cost-effective therapeutic approach must be considered by clinicians, especially those in developing countries with a high prevalence of HBV infection.

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Materials and Methods

Patients. Patients were recruited from 6 clinical centers in China. Selection criteria for patients were age of 18–70 years; chronic HBV infection, which is defined as the presence of HBsAg and HBeAg for at least 6 months prior to enrollment; serum HBV DNA level >1 × 105 copies/mL; and ALT level within a range of 2–10 times the upper limit of normal (ULN); WBC count>3.0 × 109 cells/L; granulocyte count>1.5 × 109 cells/L; and platelet count>100 × 109 platelets/L. Patients with any cause of liver disease other than chronic HBV infection, pregnant and/or breast-feeding women, individuals who have used immune regulators during the previous 6 months, or individuals who have received antiviral therapy (nucleotide analogues and IFN) during the previous 3 months of the commencement of the study were all excluded from the study. In general, 412 patients were screened, and 230 of them were found to be eligible, received therapy, and were included in the analysis of treatment efficacy. Patients who discontinued therapy were considered to be nonresponders.

The study was conducted in accordance with the ethics principles of the Declaration of Helsinki (Helsinki, Finland). Written informed consent was obtained from each participant.

Study design. This was a randomized, open-label, parallel-group study. After a 2-week screening period, during which eligibility was assessed, patients were randomly assigned to receive subcutaneous pegylated IFN-α-2b (1.0 µg/kg once per week; PegIntron; Schering Corporation) or IFN-α-2b (3 MIU 3 times per week; Intron A; Schering Corporation) for 24 weeks. During the treatment phase, efficacy and safety were assessed at weeks 1, 2, 4, 8, 12, 24, and 48. All patients completing the treatment phase were observed for an additional 24 weeks. A central computerized randomization process was employed using the randomization ratio 1:1.

Efficacy assessments. Virological response (including rate of serum HBV DNA levels <105 copies/mL and <103 copies/mL mean reduction of serum HBV DNA level from baseline), serological response (rate of HBeAg loss and seroconversion), and normalization of ALT levels were assessed at the end of treatment (week 24) and at the end of follow-up (week 48). Combined response and sustained combined response were defined as serum HBV DNA level <105 copies/mL, HBeAg loss, and normal ALT levels at the end of treatment and at the end of follow-up. Relapse was defined as a combined response at the end of treatment, but with abnormal ALT levels and serum HBV DNA level ≥105 copies/mL with or without HBeAg loss at the end of follow-up.

Laboratory and virological assays. Sera HBeAg versus anti-HBeAg and HBsAg versus anti-HBsAg were measured using AxSYM MEI kits (Abbott Laboratories). The serum HBV DNA level was determined using the Roche real-time light cycle fluorescence PCR with a lower limit of detection of 1 × 103 copies/mL (measurement units compatibility, 1IU/mL = 5.26 copies/mL). Routine biochemical and hematological tests were performed at the participating centers using automated techniques. To correct for heterogeneity arising from the use of local assays, serum ALT measurements were expressed as a ratio relative to the local upper limit of normal. Prior to commencing treatment, HBV genotype was determined for all patients with the use of an HBV genotype EIA (Institute of Immunology; Tokyo, Japan) [10].

Safety. All subjects who were assigned to randomized treatment were included in the safety assessment. Adverse effects and laboratory parameters were assessed during each clinic visit throughout the 48-week study period. Vital sign, electrocardiograph, and eye-bottom examinations were performed at baseline and at weeks 24 and 48.

Statistical analysis. Continuous variables were analyzed using an unpaired t test or Wilcoxon rank sum test, and a treatment group comparison of categorical variables was performed using the Pearson χ2 test or, if data were sparse, Fisher's exact test.

Differences between treatment groups of measurements of efficacy, which included HBV DNA response, HBeAg loss, HBeAg seroconversion, ALT level normalization, combined response, sustained combined response, and relapse, were compared using Cochran-Mantel-Haenszel statistics. A 2-way analysis of variance, with treatment, center, and treatment-by-center interaction as factors, was used to compare changes in HBV DNA levels from baseline to weeks 24 and 48 between the treatment groups. The incidence of adverse effects was compared between treatment groups using Cochran-Mantel-Haenszel statistics, controlling for center (P < .05 was considered to be statistically significant).

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Results

In total, 230 patients were enrolled in the study at 6 clinical centers in China (figure 1). An equal number of patients was assigned for each treatment arm; 115 patients were randomly assigned to receive pegylated IFN-α-2b, and 115 were randomly assigned to receive IFN-α-2b. Demographic characteristics, baseline HBV DNA level, baseline ALT level, and the percentage of patients infected with HBV genotype C were matched between the 2 treatment arms (table 1). A previous history of IFN therapy was recorded by 20 patients (17.4%) among those who received pegylated IFN-α-2b and by 10 patients (8.7%) among those who received IFN-α-2b (P = .0502).

Figure 1
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Figure 1

Patient flow in a randomized, controlled study comparing 2 treatment regimens. Six patients in the IFN-α-2b group discontinued therapy (4 had a marked increase of alanine aminotransferase level and/or total bilirubin level, and 2 were lost to follow-up because of non—study-related reasons). HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; SC, subcutaneously; ULN, upper limit of normal.

Of the patients enrolled, 170 (73.9%) were infected with HBV genotype C, and 60 (26.1%) were infected with HBV genotype B. Patients infected with genotype B were significantly younger than those infected with genotype C (mean age, 26.5 vs. 32.0 years; P < .0001). For other parameters, including sex, baseline HBV DNA level, and baseline ALT level there was no significant difference between the groups of patients with 2 genotypes.

Therapeutic efficacy of different forms of IFN-α-2b.During the treatment phase, the number of patients who responded to pegylated IFN was slightly greater than the number of those who responded to conventional IFN; however, this difference was not statistically significant. By the end of treatment, the mean reduction of HBV DNA level was 2.22 log10 copies/mL in patients who received pegylated IFN-α-2b, which was significantly greater than the level achieved in patients who received IFN-α-2b (1.66 log10 copies/mL; P = .03) (figure 2a). However, at the end of follow-up, the mean reduction in the HBV DNA level did not differ significantly between the 2 treatment arms (figure 2A and table 2). As shown in table 2, at the end of follow-up, the only difference that reached a level of significance between the 2 treatment arms was the number of patients who achieved a decrease of HBeAg, which was almost twice as high in the group receiving pegylated IFN-α-2b (24.4% vs. 13.9%; P = .04). Although, at the end of the treatment (data not shown), there was no significant difference in the number of patients experiencing a decrease of HBeAg between the 2 groups (22.6% of patients receiving pegylated IFN-α-2b vs. 17.4% of patients receiving IFN-α-2b). Rates of sustained combined response, HBeAg seroconversion, and ALT level normalization were similar for both treatment arms at the end of treatment (data not shown) and at the end of follow-up (table 2).

Figure 2
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Figure 2

A, Mean reduction of serum hepatitis B virus (HBV)–DNA levels at week 12, week 24, and week 48 from baseline in patients receiving different forms of IFN-α-2b (P = .03). B, Mean reduction of serum HBV-DNA levels at week 12, week 24, and week 48 from baseline in patients infected with HBV genotypes B and C (P = .03 and P < .0001, respectively).

Figure 3
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Figure 3

Difference of therapeutic efficacy at the end of follow-up in patients infected with hepatitis B virus (HBV) genotypes B and C on the basis of cutoff at 25 years of age. HBeAg, hepatitis B e antigen.

Table 1
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Table 1

Baseline demographic and disease characteristics of the intent-to-treat population.

Table 2
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Table 2

Virological, serological, and biochemical responses at the end of follow-up (week 48).

Two patients in the IFN-α-2b group achieved HBsAg seroconversion after 24 weeks of treatment and maintained this status through the end of follow-up at week 48. In another patient, HBsAg disappeared at week 24, but anti-HBs was not detected. This patient subsequently experienced a relapse, with the reemergence of HBsAg. All 3 patients were infected with HBV genotype B. None of the patients in pegylated IFN-α-2b group achieved HBsAg decrease or seroconversion (table 2).

HBV genotype—associated response. Significant differences were observed between the groups of patients infected with either genotype B or C (table 3). At week 48, patients with HBV genotype B responded significantly better to the therapy with regard to reduction in the HBV DNA level from baseline (-2.23 vs. -0.88 log10 copies/mL; P < .0001), HBeAg decrease (36.7% vs. 12.9%; P = .0004) and seroconversion (33.3% vs. 12.9%; P = .0012), and normalization of the ALT level (56.7% vs. 26.5%; P = .0002). Thus, sustained combined response was observed in 31.7% of the patients with HBV genotype B and 7.7% of the patients with HBV genotype C (P < .0001) (table 3).

Table 3
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Table 3

Virological, serological, and biochemical responses at the end of follow-up (week 48) in patients with different hepatitis B virus (HBV) genotypes.

The HBV DNA reduction rate was compared between different genotypes at different points (week 12 [during therapy], week 24 [at the end of treatment], and week 48 [at the end of follow-up]); we observed similar reductions at the first point, but significantly greater reduction in the group with HBV genotype B at the second and third points (figure 2B). Interestingly, the mean reduction of serum HBV DNA was remarkably stable for the group with HBV genotype B during the 24-week period following the end of therapy (-2.23 log10 copies/mL at both points), whereas a significant increase in the number of occurrences of relapse was observed in the group with HBV genotype C group (from -1.85 to -0.88 copies/mL) (figure 2B). Thus, the viral load that had been comparable between the groups of patients with HBV genotype B and HBV genotype C at the baseline (mean viral load, 7.99 and 8.03, respectively) became significantly lower in the group with HBV genotype B at week 48 (5.79 and 7.19 log10 copies/mL, respectively; P < .0001; data not shown).

With regard to the administered drug, patients infected with HBV genotype C showed significantly better response to pegylated IFN-α-2b than to conventional IFN-α-2b, as was concluded on the basis of sustained combined response achieved for either treatment arm (11.9% vs. 3.5%; P = .047; data not shown). The rate of relapse was significantly greater in patients infected with genotype C than in those infected with genotype B (77.8% vs. 27.3%; P = .018; data not shown).

Predictive factors associated with sustained combined response. With the use of multivariate statistical methods, other than the drug type (pegylated and conventional IFN-α-2b), the following host and virus factors available in this study were analyzed as independent contributors to sustained combined response: the age, sex, baseline ALT level, HBV genotype, and baseline viral load of the patients. The results obtained are summarized in table 4; patient age, which was evaluated by statistical screening (window size, 5 years; threshold, 25 years), and the viral genotype were the only 2 factors significantly associated with sustained combined response. Neither the administered form of the drug, sex, baseline ALT level, nor baseline HBV DNA level was a significant predictor for sustained combined response in the studied cohort (table 4). At the time of pretreatment, HBV DNA levels were slightly lower among patients who achieved sustained combined response than those who did not; however, the difference was not significant statistically (P = .07). Thus, sustained combined response was observed to have significantly higher frequency among patients who were ≤25 years old, irrespective of HBV genotype and the type of drug administered (26% vs. 8%; P = .0008) (figure 3). The efficacy of therapy (including serological, virological, and sustained combined response rate) was higher among patients infected with HBV genotype B for both age groups (figure 3). In total, 12 (40%) of 30 of patients who were ≤25 years old and infected with the B genotype achieved sustained combined response in this study. With respect to the treatment arm, this rate was slightly higher in the group of patients receiving pegylated IFN-α-2b than among the group of patients receiving conventional IFN-α-2b, but the difference was not significant (7 [46.7%] of 15 vs. 5 [33.3%] of 15 patients, respectively).

Table 4
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Table 4

Factors associated with sustained combined response at the end of follow-up.

Safety. In total, 75% of patients in each treatment group experienced various clinical forms of drug-related adverse effects; flulike symptoms and fever were the most common. However, only 4 patients (1.7%) in our study discontinued treatment because of drug-related adverse effects. These included 2 patients with an increased ALT level who experienced nausea and vomiting, 1 patients with elevated ALT and total bilirubin levels, and 1 patient with an elevated total bilirubin level. All of these patients received IFN-α-2b. Only 1 patient who received pegylated IFN-α-2b experienced nausea and vomiting; however, because of the dynamic clinical evaluation, discontinuation of treatment was not required. Two other patients who received IFN-α-2b did not complete the treatment phase because of non—study-related reasons.

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Discussion

According to the most recent recommendations for patients with chronic HBV infection, IFN-α-2b should be administered at a dosage of 30–35 MIU per week (5 MIU per day or 10 MIU every 3 days) [2]. In our study, patients received 3 MIUs of IFN-α-2b 3 times per week (9 MIUs per week total), which is less than one-third of the recommended dosage for IFN-α-2b. One dose of pegylated IFN in our study was 1.0 µg/kg per week (65 µg per week on average). In previous reports, pegylated IFN-α-2b was administered at a dosage of 1.5 µg/kg per week for patients with body weight <65 kg or 100 µg per week for those with a body weight ≥65 kg as a monotherapy during an 8-week period and then in combination with lamivudine (100 mg per day orally) for 24 weeks. After the 24 weeks of combination therapy, lamivudine monotherapy was administered for an additional 28 weeks [11] (or 100 µg per week during a 32-week period); thereafter, the dosage was reduced to 50 µg per week for the remaining 20 weeks (total, 52 weeks) [7, 12]. The studies mentioned above indicated that lamivudine, but not IFN, provided benefit with combination therapy with regard to sustained combined response. The following factors were analyzed: drug (pegylated and nonpegylated IFN-α-2b), patient (age, sex, and baseline ALT levels), and virus (baseline HBV DNA level and genotype).

Previously, comparative analyses between the effects of pegylated versus nonpegylated forms of IFN-α-2a on HBeAg-positive patients with chronic HBV infection indicated a significantly higher sustained combined response (HBV DNA level, <5 × 105 copies/mL; HBeAg level decrease; and ALT level normalization) rate in pegylated form (24% vs. 12%; P = .036) [13]. To our knowledge, there was no study with a head-to-head comparison of pegylated and nonpegylated forms of IFN-α-2b. In the present study, our results indicate that the reduction in mean serum HBV DNA level during treatment and the decrease in the HBeAg level at the end of follow-up were significantly greater in patients who received pegylated IFN-α-2b than in those who were given IFN-α-2b; however, there was no significant difference in the rate of sustained combined response. This discrepancy with the previous report might be attributable to the lower dose regimen administered during our study.

Interestingly, it was evident that IFN-α-2b was more effective for patients infected with HBV genotype B than those infected with the HBV genotype C. Although there was little difference between the groups at the end of the treatment phase, follow-up data indicated that the effects of treatment were more sustained in patients infected with HBV genotype B. This observation is consistent with other reports that indicated that HBV genotypes C and D are more resistant to IFN-α-2b therapy than HBV genotypes A and B [14]. Moreover, the HBV genotype was shown to be an independent factor predictive for sustained combined response in multivariate statistical analysis. Another independent factor associated with sustained combined response was patient age with a statistical cutoff at 25 years. In this study, 40% of the patients infected with HBV genotype B that were <25 years of age achieved a sustained combine response after 24 weeks of a low-dose regimen that was comparable or even higher than the results obtained with standard doses [4, 7]. On the other hand, the rate of clinically significant adverse effects leading to the discontinuation of treatment in the present study was negligible (1.7%).

It was previously reported that, because of high rates of natural seroconversion and self-limited elimination of HBV, it is not cost-effective for younger patients to start early treatment [15, 16]. However, there was an observed association of HBV genotype Ba with younger age among patients with hepatocellular carcinoma [17, 18]. In this regard, the direct growth-suppression effect of IFN-α-2b on cancer cells [19] gives this drug an advantage in preventing the development of hepatocellular carcinoma, not only etiologically (by virus suppression), but also pathogenetically (by inhibition of the cell cycle). Furthermore, according to a recent report from Europe, HBeAg decrease was achieved in 44% of patients with HBV genotype B after treatment with 100 µg per week for 32 weeks, followed by 50 µg per week for 20 weeks [20]. In our study, the rate did not differ significantly (pegylated IFN-α-2b, -42%; IFN-α-2b, -31%; and combined, -36.7%), although the average dosage was 65 µg per week for pegylated IFN-α-2b. Thus, the cost-effectiveness of early treatment should be carefully evaluated for this particular category.

In conclusion, we found that in Chinese patients with HBeAg-positive chronic hepatitis B, viral genotype and patient age were strongly associated with the therapeutic efficacy of a low-dose, short-term IFN-α-2b regimen. Furthermore, 40% of the patients infected with HBV genotype B who were ≤25 years of age were able to achieve a sustained combined response, and the adverse effects were negligible. Additional case-control studies are required to confirm the cost benefit of low-dose, short-term therapy among patients with different HBV genotypes.

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Acknowledgments

We thank Edwin L. Carty (Gakken Publisher, Tokyo, Japan) and 2 anonymous reviewers for their critical reading of the manuscript and for their suggestions.

Potential conflicts of interest. All authors: no conflicts.

  • Received August 11, 2006.
  • Accepted October 19, 2006.
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  1. Clin Infect Dis. (2007) 44 (4): 541-548. doi: 10.1086/511042
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