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 Table of Contents  
Year : 2018  |  Volume : 131  |  Issue : 14  |  Page : 1645-1651

Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients: A Randomized, Multicenter, Phase IIIb Open-Label Study (POTENT Study)

1 Department of Internal Medicine, Hanyang University Seoul Hospital, Hanyang University, Seoul 04763, Korea
2 Department of Internal Medicine, Nowon Eulji Hospital, Eulji University, Seoul 01830, Korea
3 Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University, Guri 11923, Korea
4 Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, SoonChunHyang University, Bucheon 14584, Korea
5 Department of Internal Medicine, SoonChunHyang University Cheonan Hospital, SoonChunHyang University, Cheonan 31151, Korea
6 Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul 02453, Korea
7 Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon 24252, Korea
8 Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University, Seoul 05355, Korea
9 Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University, Seoul 06273, Korea
10 Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea
11 Department of Internal Medicine, Sanggye Paik Hospital, Inje University, Seoul 01757, Korea
12 Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Korea
13 Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University, Daegu 42415, Korea
14 Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University, Yangsan 50612, Korea
15 Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University, Pusan 49267, Korea
16 Department of Internal Medicine, Dong A University Medical Center, Dong A University, Pusan 49201, Korea
17 Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University, Wonju 26426, Korea
18 Department of Internal Medicine, Haeundae Paik Hospital, Inje University, Pusan 48108, Korea
19 Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University, Anyang 14068, Korea
20 Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Sungkyunkwan University, Suwon 16419, Korea
21 Clinical Research Center, Asan Medical Center, Seoul 05505, Korea

Date of Submission13-Mar-2018
Date of Web Publication4-Jul-2018

Correspondence Address:
Dr. Joo Hyun Sohn
Department of Internal Medicine, Hanyang University Guri Hospital, 153 Gyeongchun-ro, Guri 11923
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0366-6999.235880

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Background: Until now, various types of combined therapy with nucleotide analogs and pegylated interferon (Peg-INF) in patients with hepatitis B patients have been tried. However, studies regarding the benefits of de novo combination, late-add on, and sequential treatment are very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment.
Methods: Between June 2010 and June 2015, hepatitis B e antigen (HBeAg)-positive patients (n = 162) received Peg-IFN for 48 weeks (mono-treatment group, n = 81) and entecavir (ETV) for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy (sequential treatment group, n = 81). The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher's exact test, and regression analysis.
Results: HBeAg seroconversion rate (18.2% vs. 18.2%, t = 0.03, P = 1.000) and seroclearance rate (19.7% vs. 19.7%, t = 0.03, P = 1.000) were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase (ALT) normalization (45.5% vs. 54.5%, t = 1.12, P = 0.296) and serum hepatitis B virus (HBV)-DNA <2000 U/L (28.8% vs. 28.8%, t = 0.10, P = 1.000) was not different in sequential and mono-treatment groups at 24 weeks of Peg-INF. Viral response rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L) was not different in the two groups (12.1% vs. 16.7%, t = 1.83, P = 0.457). Baseline HBV-DNA level (7 log10U/ml vs. 7.5 log10U/ml, t = 1.70, P = 0.019) and hepatitis B surface antigen titer (3.6 log10U/ml vs. 4.0 log10U/ml, t = 2.19, P = 0.020) were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively.
Conclusions: The current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens.
Trial Registration: ClinicalTrials.gov, NCT01220596; https://clinicaltrials.gov/ct2/show/NCT01220596?term=NCT01220596&rank=1.

Keywords: Entecavir; Hepatitis B; Peginterferon Alfa-2a

How to cite this article:
Jun DW, Ahn SB, Kim TY, Sohn JH, Kim SG, Lee SW, Kim BH, Kim DJ, Kim JK, Kim HS, Hwang SG, Choi WC, Tak WY, Lee HJ, Yoon KT, Yun BC, Lee SW, Baik SK, Park SH, Park JW, Park SJ, Lee JS. Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients: A Randomized, Multicenter, Phase IIIb Open-Label Study (POTENT Study). Chin Med J 2018;131:1645-51

How to cite this URL:
Jun DW, Ahn SB, Kim TY, Sohn JH, Kim SG, Lee SW, Kim BH, Kim DJ, Kim JK, Kim HS, Hwang SG, Choi WC, Tak WY, Lee HJ, Yoon KT, Yun BC, Lee SW, Baik SK, Park SH, Park JW, Park SJ, Lee JS. Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients: A Randomized, Multicenter, Phase IIIb Open-Label Study (POTENT Study). Chin Med J [serial online] 2018 [cited 2018 Dec 19];131:1645-51. Available from: http://www.cmj.org/text.asp?2018/131/14/1645/235880

Dae Won Jun and Sang Bong Ahn contributed equally to this work.

  Introduction Top

The current recommended standard therapy for chronic hepatitis B comprises of the interferon monotherapy or the oral antiviral drugs.[1],[2] The interferon therapy is known to inhibit hepatitis B virus (HBV) protein synthesis and to reduce intrahepatic covalently closed circular DNA (cccDNA), thereby inducing hepatitis B surface antigen (HBsAg) loss.[3],[4] On the other hand, although the oral antiviral therapy effectively suppresses viral replication in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients, HBeAg/HBsAg loss or seroconversion rates are still low.[5],[6] Many researchers had tried to improve the efficacy using various combinations such as de novo combination treatment, sequential, or the late and add-on treatments.[7],[8]

Until now, the scarcity of sequential treatment studies and lack of supporting data limit the application of sequential treatment to be recommended clinically. For instance, for the first time, Serfaty et al.[9] performed sequential treatment using lamivudine and interferon in HBV patients. The antiviral response including HBsAg seroconversion was more in sequential treatment group compared to oral antiviral mono-treatment group. The number of studies applying the sequential nucleotide analogs (NUCs) to pegylated interferon (Peg-INF) strategy was limited, and the following two studies did not support previous result.[10] The current randomized controlled study investigated the treatment efficacy and adverse effects of sequential Peg-IFN treatment with short-term use of entecavir (ETV) for 12 weeks.

  Methods Top

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Hanyang University Hospital Institutional Review Board/Ethics Committee (IRB No. HYUH 20104003).

All patients signed an informed consent prior to study participation and all centers were monitored by an independent institution.

Study design

The current phase IIIb, randomized, open-label study was conducted in ten centers of South Korea between June 2010 and June 2015. Patients were divided into Peg-IFN monotherapy (Peginterferon Alfa-2α, Pegasys, F. Hoffmann-La Roche Ltd., Basel, Switzerland) 180 μg once weekly for 48 weeks and sequential treatment groups (ETV; Baraclude, Bristol-Myers Squibb, New York, USA) 0.5 mg once daily for 4 weeks followed by a combination of ETV and Pegasys (for 8 weeks), followed by Pegasys alone (for 40 weeks). The randomization was performed using the central computer.

During the treatment period of 48 weeks (+8 weeks), the patients were followed up at 4th, 8th, 12th, 24th, 36th, and 48th week. During each visit, biochemical and hematological assessments were made.

Inclusion and exclusion criteria

Individuals aged 18 years or older with chronic hepatitis B (i.e., HBsAg positive for more than 6 months, positive HBeAg or negative HBeAg, or detectable HBV DNA (>100,000 copies/ml by polymerase chain reaction], or anti-HBs negative) and with serum alanine aminotransferase (ALT) level >2 times the upper normal limit (UNL) but <10 times the UNL were included.

The following individuals were excluded from the study: individuals receiving antiviral treatment for chronic hepatitis B and those with positive results for hepatitis A virus IgM antibody (Ab), hepatitis C virus (HCV)-RNA or HCV-Ab, and hepatitis D virus Ab or human immunodeficiency virus Ab; patients diagnosed with hepatoma or suspected liver malignancy, or individuals with <1500 neutrophils/mm 3 or <90,000 thrombocytes/mm 3, or individuals with more than 1.5 times the UNL serum creatinine, or with signs of alcohol or drug abuse within <1 year before participating in study, and patients with pregnancy or lactation were excluded from the study. Individuals with a history of the following diseases were also excluded: serious mental disorders, especially depression, immunological infection, decompensated cirrhosis events (Child Pugh B-C), chronic liver failure, autoimmune hepatitis, alcoholic liver disease, chronic respiratory disorders, serious heart diseases, or serious seizure disorder. Moreover, patients contraindicated to Peg-IFN treatment including a history of thyroid disease, or taking anti-seizure drug, or received organ transplantation, were also excluded from the study.

Efficacy analysis

The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The secondary endpoints were changes in HBsAg titer, HBeAg-negative chronic infection status (combined HBeAg seroconversion and HBV DNA <2000 U/ml), serum HBV DNA <300 copies/ml, ALT normalization, and HBsAg loss. Primary and secondary efficacy indexes were analyzed at the end of treatment and at the end of follow-up. Responder was defined as HBeAg-negative chronic infection status (HBeAg seroconversion + HBV DNA <2000 U/ml).

Safety analysis

After drug administration, safety analysis was performed on all patients at least once. Measures of safety included adverse events, hematologic measurements, clinical chemical measurements, and vital signs. The association between AEs and drug therapy was determined by researchers at each center. The preferred terms for AEs and categorization were adopted from the Medical Dictionary for Drug Regulatory Affairs.

Dose adjustment guideline

Pegasys dose was de-escalated or temporarily discontinued if neutrophil counts were <750/mm 3 or <500/mm 3, respectively. The treatment was restored when the neutrophil count increased to >1000/mm 3. During treatment restoration, Pegasys dose (90 μg) and neutrophil count were carefully monitored. Moreover, at thrombocyte count <50,000/mm 3, Pegasys dose was de-escalated (90 μg), while at <25,000/mm 3, the dose was stopped. Whenever necessary, the first de-escalation was performed using 135 μg Pegasys (75%), while the second de-escalation was performed using 90 μg Pegasys (50%).

Statistical analysis

An intention-to-treat (ITT) analysis group included all patients who were randomly allocated and administered with Peg-INF at least twice during the clinical trial. The randomly allocated treatment groups were analyzed, and the primary and secondary variables for effectiveness were analyzed. The primary endpoint was analyzed using the Chi-square test, Fisher's exact test, and regression analysis. Patient characteristics were analyzed using Student's t-test and its nonparametric equivalent (Wilcoxon Rank-Sum test). SPSS for Windows version 16.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.

  Results Top

Study participants

A total of 186 patients were screened. Among the screened patients, 24 patients who were unable to satisfy the study criteria were excluded [Figure 1]. The remaining 162 patients were randomly divided into interferon monotherapy and sequential therapy groups. In both the groups, 15 patients were eliminated due to follow-up loss, side effects, treatment discontinuation, protocol violation, or declined participation.
Figure 1: Flow diagram of enrolled patients in the study.

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Basic characteristics

There was no difference in average age of patients in both the interferon monotherapy and the sequential therapy groups [Table 1]. One cirrhotic patient was included in the interferon monotherapy group (1.2%), while sequential therapy group had three cirrhotic patients (3.7%). There was no difference in HBV-DNA and HBsAg titers prior to treatment in both groups.
Table 1: Baseline clinical characteristics of patients in the study

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Viral response rate by intention-to-treat analysis

An ITT analysis was carried out among 162 randomly allocated patients. There was no difference in HBeAg seroconversion rates between the two groups with 16.0% (13/81) and 14.8% (12/81) (t = 0.03, P = 0.828), respectively. There was also no difference in response rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L) between the interferon monotherapy and sequential therapy groups with 11.1% (9/81) and 13.6% (11/81) (t = 1.60, P = 0.633), respectively.

Viral response rate per protocol analysis

Among the 162 patients, the per protocol analysis was applied on 132 patients who were treated according to the study protocol [Table 2]. After 12-week treatment, the interferon monotherapy group had more nonresponders compared to sequential therapy group. After 24 weeks, there was no difference in HBeAg seroclearance, HBeAb seroconversion, HBV DNA <2000 U/ml, HBV DNA <60 U/ml, responder rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L), and ALT normalization between the two groups. Overall, during the entire treatment duration, there was no significant difference in HBV DNA and HBsAg levels between the two groups [Figure 2]. No HBsAg loss was observed in both the groups after 24-week treatment.
Table 2: Clinical outcomes between peginterferon therapy and sequential treatment in per protocol analysis

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Figure 2: Comparison of HBV DNA level (a) and HBsAg level (b) between sequential therapy and monotherapy groups. HBV: Hepatitis B virus; DNA: Deoxyribonucleic acid; HBsAg: Hepatitis B surface antigen.

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Adverse effects

Among the 162 participants, 69 patients experienced drug-related adverse effects, while 44 patients complained about side effects greater than grade II defined by the World Health Organization. However, there was no difference between the two groups. The interferon monotherapy group had more severe adverse reactions compared to sequential therapy group. No drug-related mortality was observed during the study [Table 3]. The dose adjustments were made in five patients in interferon monotherapy group and two patients in sequential therapy group.
Table 3: Adverse events between peginterferon therapy and sequential treatment in randomized patients

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Predicting factors for viral response

Among the 132 study participants, HBeAg seroconversion and HBV DNA concentration in serum of 19 patients remained below 2000 U/ml. Predicting factors for viral response (HBeAg seroconversion and HBV DNA <2000 U/ml) in interferon-based treatment were analyzed [Table 4]. Multivariate analysis showed that the baseline HBsAg titer was the only independent predictor of (<4 log10U/ml) HBeAg seroconversion and HBV DNA <2000 U/ml in interferon-based treatment. The predicting factors determining responders and nonresponders were compared within the groups [Table 5]. Among the patients receiving Peg-IFN monotherapy, the low baseline HBV DNA levels were observed in both responders and nonresponders. In the sequential therapy group, the low baseline HBsAg titer, HBV DNA reduction after 12-week treatment, serves as a predictor of HBeAg seroconversion and HBV DNA <2000 U/ml.
Table 4: Predictors of response in interferon-based treatment

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Table 5: Predictors of response using baseline parameters and on-treatment parameters

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  Discussion Top

The current study found that there was no difference in efficacy and adverse effects between the sequential Peg-IFN treatment group and Peg-IFN mono-treatment group. A number of published studies compared the effectiveness of combined Peg-IFN and NUC in treating hepatitis B. The first pivotal study showed no difference in HBsAg loss among the Peg-IFN + lamivudine de novo combination therapy group and lamivudine and Peg-IFN monotherapy groups.[11] ARES study evaluated the efficacy of late “add-on” strategy. Add-on Peg-INF to ETV for 24 weeks showed better viral kinetics. However, there was no difference in HBeAg loss which was the primary endpoint.[12] NUC analogs of short-term pretreatment and late switch to Peg-INF regimens were adopted to evaluate the treatment effects on hepatitis B. However, to date, there are a limited number of studies utilizing the sequential NUC to Peg-INF strategy. For instance, there is only one published study regarding sequential NUC to Peg-INF strategy, which reported results similar to short-term ETV treatment.[10] In this study, 12-week ETV pretreatment could not increase Peg-IFN's HBeAg seroconversion rate (18.2%). Such difference is believed to be attributable to the fact that the current study is an investigator-initiated trial carried out in a real-life setting; dropout rate is high and genotype C is the predominant HBV genotype in Korea.[13]

The level and changes of HBV DNA at 12th week treatment were statistically significant (P< 0.001 and P = 0.001, respectively). In the OSST trial, ETV treatment led to HBe antigen loss; when HBsAg level was <1500 U/ml, treatment switching to Peg-IFN produced a great therapeutic effect with 22.2% HBsAg loss and 33.3% of HBeAg seroconversion.[14] Marcellin et al.[15] reported that 48-week combination therapy (Peg-IFN and tenofovir) had better results in HBsAg seroclearance (6.5%) than the 16-week combination therapy with Peg-IFN and tenofovir or the tenofovir monotherapy. Therefore, it is desirable to treat with interferon after full NUC treatment or add Peg-IFN and NUC for a longer period of time in order to enhance therapeutic action. It is also better to apply combination therapy more aggressively in patients with low baseline HBsAg level or high DNA-decreasing reduction at the 12th week of treatment.

There was no significant difference in the safety profile of the current study and other previous monotherapy studies or Peg-IFN and ETV combination therapies. The limitations of the current study are as follows: first, the 6-month follow-up period was relatively short. Different results might have been produced if the follow-up period was prolonged. Second, HBV genotype test was not performed in the study groups. Previous studies suggest that HBsAg kinetics and HBeAg seroconversion rate are likely to vary according to genotypes. However, it would be impossible to find the difference by genotypes even though DNA genotype testing was carried out. The distribution of genotype C is nearly 100% in South Korea.[16]

Consequently, the current study found that pretreatment with ETV did not enhance the therapeutic benefit of Peg-IFN compared to monotherapy. There was no difference in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between monotherapy and sequential therapy groups. Otherwise, baseline HBsAg titer (<4 log10U/ml) was a predictor of responder in Peg-INF base treatment strategy.

Financial support and sponsorship

This study was supported by a grant from Roche.

Conflicts of interest

There are no conflicts of interest.

  References Top

European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-98. doi: 10.1016/j.jhep.2017.03.021.  Back to cited text no. 1
Korean Association for the Study of the Liver. KASL clinical practice guidelines: Management of chronic hepatitis B. Clin Mol Hepatol 2016;22:18-75. doi: 10.3350/cmh.2016.22.1.18.  Back to cited text no. 2
Tjwa ET, van Oord GW, Hegmans JP, Janssen HL, Woltman AM. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 2011;54:209-18. doi: 10.1016/j.jhep.2010.07.009.  Back to cited text no. 3
Sonneveld MJ, Zoutendijk R, Hansen BE, Janssen HL. Pegylated interferon results in higher serological, but not virological, response rates when compared to continuous entecavir. Antivir Ther 2012;17:1605-8. doi: 10.3851/IMP2319.  Back to cited text no. 4
Reijnders JG, Perquin MJ, Zhang N, Hansen BE, Janssen HL. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology 2010;139:491-8. doi: 10.1053/j.gastro.2010.03.059.  Back to cited text no. 5
Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011;140:132-43. doi: 10.1053/j.gastro.2010.10.011.  Back to cited text no. 6
Piratvisuth T, Lau G, Chao YC, Jin R, Chutaputti A, Zhang QB, et al. Sustained response to peginterferon alfa-2a (40kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Hepatol Int 2008;2:102-10. doi: 10.1007/s12072-007-9022-5.  Back to cited text no. 7
Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, et al. Arandomized, controlled trial of combination therapy for chronic hepatitis B: Comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142:240-50. doi: 10.7326/0003-4819-142-4-200502150-00006.  Back to cited text no. 8
Serfaty L, Thabut D, Zoulim F, Andreani T, Chazouillères O, Carbonell N, et al. Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: Results of a pilot study. Hepatology 2001;34:573-7. doi: 10.1053/jhep.2001.26819.  Back to cited text no. 9
Xie Q, Zhou H, Bai X, Wu S, Chen JJ, Sheng J, et al. Arandomized, open-label clinical study of combined pegylated interferon alfa-2a (40KD) and entecavir treatment for hepatitis B “e” antigen-positive chronic hepatitis B. Clin Infect Dis 2014;59:1714-23. doi: 10.1093/cid/ciu702.  Back to cited text no. 10
Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-95. doi: 10.1056/NEJMoa043470.  Back to cited text no. 11
Brouwer WP, Xie Q, Sonneveld MJ, Zhang N, Zhang Q, Tabak F, et al. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study). Hepatology 2015;61:1512-22. doi: 10.1002/hep.27586.  Back to cited text no. 12
Bae SH, Yoon SK, Jang JW, Kim CW, Nam SW, Choi JY, et al. Hepatitis B virus genotype C prevails among chronic carriers of the virus in Korea. J Korean Med Sci 2005;20:816-20. doi: 10.3346/jkms.2005.20.5.816.  Back to cited text no. 13
Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, et al. Switching from entecavir to pegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomised open-label trial (OSST trial). J Hepatol 2014;61:777-84. doi: 10.1016/j.jhep.2014.05.044.  Back to cited text no. 14
Marcellin P, Ahn SH, Chuang WL, Hui AJ, Tabak F, Mehta R, et al. Predictors of response to tenofovir disoproxil fumarate plus peginterferon alfa-2a combination therapy for chronic hepatitis B. Aliment Pharmacol Ther 2016;44:957-66. doi: 10.1111/apt.13779.  Back to cited text no. 15
Cho JH, Yoon KH, Lee KE, Park DS, Lee YJ, Moon HB, et al. Distribution of hepatitis B virus genotypes in Korea. Korean J Hepatol 2009;15:140-7. doi: 10.3350/kjhep.2009.15.2.140.  Back to cited text no. 16


  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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