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Hepatology Research 2014
doi: 10.1111/hepr.12284
Original Article
Effect of HLA-DP and IL28B gene polymorphisms on response to interferon treatment in hepatitis B e-antigen seropositive chronic hepatitis B patients Lin Cheng,1,2 Xiaowen Sun,1,2 Shun Tan,1,2 Wenting Tan,1,2 Yunjie Dan,1,2 Yi Zhou,1,2 Qing Mao1,2 and Guohong Deng1,2,3 1 Department of Infectious Diseases, Southwest Hospital, 3Institute of Immunology, Third Military Medical University, and 2Chongqing Key Laboratory of Infectious Diseases, Chongqing, China
Aim: The reason why the majority of chronic hepatitis B (CHB) patients do not respond to conventional interferon (IFN)-α or pegylated interferon (PEG IFN) treatment has not been formally demonstrated. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) and response to IFN-α or PEG IFN therapy in Chinese patients with CHB. Methods: Four SNPs among the HLA-DPA1, HLA-DPB1 (rs3077 and rs9277535) and IL28B (rs12979860 and rs8099917) regions were genotyped using the MGB-TaqMan SNP genotyping assay in 144 hepatitis B e-antigen (HBeAg) seropositive CHB patients who had received 6–12 months IFN-α or PEG IFN treatment. Patients were classified as responders who achieved any of the four targets: (i) the loss of HBeAg; (ii) anti-HBe seroconversion; (iii) suppression of hepatitis B virus (HBV) DNA level to below 3 log of baseline; and (iv) alanine aminotransferase normalization.
INTRODUCTION
H
EPATITIS B IS a viral infection that attacks the liver and can cause chronic disease, an estimated 2 billion people worldwide have been infected with the hepatitis B virus (HBV) and more than 240 million have chronic (long-term) liver infections. Chronic infection with HBV is a key cause of severe hepatitis B, liver cirrhosis and hepatocellular carcinoma (HCC), which
Correspondence: Dr Guohong Deng, Department of Infectious Diseases, Southwest Hospital, and Institute of Immunology, Third Military Medical University, Chongqing, 400038, China. Email: [email protected] Received 23 September 2013; revision 5 November 2013; accepted 26 November 2013.
© 2013 The Japan Society of Hepatology
Results: By multivariate analysis at 6 months of therapy and 6 months post-therapy, the results showed that rs3077-GG genotype was independently associated with higher HBeAg loss rate and anti-HBe seroconversion rate, and rs9277535-GG genotype was independently associated with decline of HBV DNA level. However, we did not observe the significant association between SNP near IL28B and the response to IFN-α or PEG IFN treatment.
Conclusion: This study suggested that HLA-DPA1 and HLADPB1 variants were significantly associated with HBeAg loss, anti-HBe seroconversion and HBV DNA level suppression in HBeAg seropositive CHB patients who received IFN-α or PEG IFN treatment. Key words: hepatitis B virus, HLA-DP, IL28B, interferon, single nucleotide polymorphisms
leads to high mortality.1 At present, conventional interferon (IFN)-α, pegylated interferon (PEG IFN) and nucleoside analogs (NUC) have been approved for the treatment of chronic HBV infection.2 Compared with NUC, IFN-α or PEG IFN treatment remains an attractive anti-HBV strategy because it provides a lower rate of relapse and can achieve HBV surface antigen (HBsAg) clearance.3,4 However, IFN-α- or PEG IFN-based therapy is modestly effective in hepatitis B e-antigen (HBeAg) loss or seroconversion in HBeAg positive patients; thus, restricted efficacy in only a proportion of patients (15– 41%) who show a response.5 Furthermore, IFN-α or PEG IFN can cause several side-effects during treatment,6 and also there are significant costs. Selection of patients with the highest probability of response for optimal use of this agent in clinical practice is essential.
1
2 L. Cheng et al.
There have been many attempts to identify pretreatment predictors of a response, resulting in the identification of high alanine aminotransferase (ALT) levels, low HBV DNA and virus genotype as significant predictors.3,4 However, all these markers are quite weak predictors of response at the individual level. Recently, a genome-wide association study identified single nucleotide polymorphisms (SNPs) located within the human leukocyte antigen (HLA) class II genes HLA-DPA1 and HLA-DPB1 to be associated with chronic hepatitis B (CHB).7 Replication studies performed on two of these SNPs (rs3077 and rs9277535) confirmed and strengthened results from the genome-wide association studies.8–10 Class II HLA genes encode proteins expressed on the surface of antigen-presenting cells such as macrophages, dendritic cells and B cells, and thereby have a critical role in presentation of antigens to CD4+ T-helper lymphocytes. HLA genes have many structural variants that have been linked to immune response to infectious agents,11 whether class II HLA gene polymorphisms associated with response to IFN-α- or PEG IFN-based treatment in CHB patients needs further investigation. In addition, the HCV field has been revolutionized by the discovery that IL28B polymorphisms can predict a sustained virological response to PEG IFN-based regimens in patients infected with HCV12–15 lately. Despite differences between HCV and HBV, investigators were tempted to test whether IL28B polymorphisms could also predict response to IFN-α- or PEG IFN-based treatment in HBV patients. Currently, data on IL28B polymorphisms and response to IFN-α or PEG IFN in HBV are scarce and conflicting,16–20 study of the relationship between IL28B polymorphisms and response to IFN-αor PEG IFN-based therapy in CHB patients in Chinese would be meaningful.
METHODS
Hepatology Research 2014
hepatitis C or D virus or HIV, association with other severe underlying disease were excluded.
Definitions of treatment responses The study had four predetermined primary measures of efficacy assessed at 6 months of therapy and 6 months post-therapy as follows; (i) the loss of HBeAg; (ii) antiHBe seroconversion; (iii) decline of HBV DNA level to below 3 log of baseline; and (iv) ALT normalization.5 Patients were classified as responders who achieved any of the four targets. Conversely, patients were classified as non-responders who did not.
Serum assays Blood samples were obtained from 144 persistent chronic HBV carriers (104 males and 40 females), 81 patients were treated with PEG IFN and 63 with IFN-α. HBV markers including HBeAg and anti-HBe antibody were tested by the automatic electrochemiluminescence immunoassay analyzer at baseline, 3 months and 6 months of therapy, and 3 months and 6 months off therapy. Serum HBV DNA load was measured by the LightCycler48 Real-time PCR instrument (Roche, Basel, Switzerland), and plasma ALT was examined by Hitachi 7060-010 automatic biochemistry analyzer (Hitachi, Tokyo, Japan).
Genotyping Genomic DNA from patients was extracted from peripheral blood using standard methods. MGB-TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were used for the detection of the referenced SNPs in HLA-DP (rs3077 and rs9277535) and near the IL28B gene (rs12979860 and rs8099917) on the chromosome.22 For allelic discrimination, genotyping of each sample was automatically attributed by the Roch 480II system (Roche).
Patients
P
ATIENTS WITH CHB who had received IFNα or Peg-IFN treatment for 6–12 months were recruited between December 2009 and November 2012 at the Department of Infectious Disease, Southwest Hospital, Chongqing, China. All patients were positive for HBsAg and HBeAg, and none of them had received standard IFN before. According to the recommendation of the Asia–Pacific consensus statement on the management of CHB, most of our patients received IFN-α or PEG IFN treatment for 6 months and only 11 patients received IFN-α or PEG IFN for 12 months.21 Cirrhosis, hepatic carcinoma, autoimmune hepatitis, co-infection with
© 2013 The Japan Society of Hepatology
Statistical analysis Statistical analysis was performed using SPSS version 18.0 software (SPSS, Chicago, IL, USA). The χ2-test was performed to examine the differences of baseline factors and the allele frequency between groups. Binary logistic regression analysis was performed to adjust risk factors such as sex, age, IFN type, baseline ALT level, HBV DNA level and HBV genotype. The association between genotyped polymorphisms and responses was estimated by P-values, odds ratios (OR) and 95% confidence intervals (95% CI), and P < 0.05 in a two-sided test was considered statistically significant.
Hepatology Research 2014
RESULTS
T
HE DEMOGRAPHIC DATA of the 144 HBeAg positive CHB patients are shown in Table 1. The overall response rates of HBsAg loss, HBeAg loss, anti-HBe seroconversion, decline of HBV DNA level to below 3 log of baseline and ALT normalization were 4.2%, 23.6%, 31.9%, 59.0% and 34.7% at 6 months of therapy, and 4.2%, 34.7%, 34.7%, 67.4% and 47.2% at 6 months off therapy, respectively. At 6 months of therapy and 6 months post-therapy, the differences of baseline factors between groups including sex, mean age, IFN type, baseline ALT level, baseline HBV DNA level, HBV genotype and the allele frequency for the four SNP were all analyzed by χ2-tests, with the results shown in Table 2 and Table 3. For the loss of HBeAg, the frequency of G allele of rs3077 was significantly higher in responders than in non-
HLA-DP, IL28B gene polymorphisms and IFN 3
responders (80.9% vs 68.8%, P = 0.037; 82.0% vs 65.4%, P = 0.002). For anti-HBe seroconversion, the G allele frequency of rs3077 was significantly higher in responders than in non-responders (82.6% vs 65.8%, P = 0.003; 81.0% vs 66.0%, P = 0.006). For HBV DNA suppression, the frequency of G allele of rs9277535 was significantly higher in responders than in nonresponders (77.6% vs 66.9%, P = 0.045; 77.8% vs 63.8%, P = 0.013). For ALT normalization at 6 months off therapy, the frequencies of rs12979860 C allele and rs8099917 T allele were significantly higher in responders than in non-responders (both P = 0.014). The multivariate analysis enrolled the baseline factors with P < 0.5 in the prior logistic regression, including sex, age, IFN type, baseline ALT level and HBV DNA level, as shown in Table 4. At 6 months of therapy and 6 months post-therapy, the results showed that rs3077-GG genotype was independently associated with
Table 1 Distribution of selected characteristics in chronic hepatitis B patients treated with conventional IFN-α or PEG IFN PEG IFN (n = 81) Sex Female, n (%) Male, n (%) Age Mean, years (1SD) Median, years (range) Pre-therapy ALT level Mean, IU/L (1SD) 1–2 × ULN (40–80 IU/L), n (%) 2–5 × ULN (80–200 IU/L), n (%) >5 ULN (>200 IU/L), n (%) Serum HBV DNA level Mean, log IU/mL (1SD) Median, log IU/mL (range) HBV genotype B, n (%) C, n (%) 6 months of therapy HBsAg loss, n (%) HBeAg loss, n (%) Anti-HBe seroconversion, n (%) HBV DNA decline 33 log, n (%) ALT normalization, n (%) 6 months off therapy HBsAg loss, n (%) HBeAg loss, n (%) Anti-HBe seroconversion, n (%) HBV DNA decline 33 log, n (%) ALT normalization, n (%)
IFN-α (n = 63)
25 (30.9) 56 (69.1)
15 (23.8) 48 (76.2)
27.8 (17.7) 26 (16–56)
25.2 (17.8) 24 (4–41)
190.5 (1121.7) 6 (7.4) 48 (59.3) 27 (33.3)
170.7 (193.1) 3 (4.8) 42 (66.7) 18 (28.6)
7.6 (10.8) 7.3 (5.0–8.6)
7.8 (10.1) 7.3 (4.1–8.9)
39 (48.1) 19 (23.5)
33 (52.4) 9 (14.3)
1 (1.2) 17 (21.0) 25 (30.9) 51 (63.0) 28 (34.6)
5 (7.9) 17 (27.0) 21 (33.3) 34 (54.0) 22 (34.9)
1 (1.2) 27 (33.3) 25 (30.9) 61 (75.3) 41 (50.6)
5 (7.9) 23 (36.5) 25 (39.7) 36 (57.1) 27 (42.9)
ALT, alanine aminotransferase; HBeAg, hepatitis B e-antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN-α, conventional interferon α; PEG IFN, pegylated interferon; SD, standard deviation; ULN, upper limit of normal.
© 2013 The Japan Society of Hepatology
17 17 1 (2.9) 20 (58.8) 13 (38.3) 8 (23.5) 26 (76.5) 13 9 4 5 25 0.809 2 11 21 0.779 0 2 32 0.029 0 2 32 0.029
8 (7.3) 70 (63.6) 32 (29.1) 12 (10.9) 98 (89.1) 59 19 23 24 63 0.688 4 54 52 0.718 1 12 97 0.064 1 12 97 0.064
6 (17.6) 28 (82.4) 25.6 (18.9)
Responder (n = 34)
64 46
34 (30.9) 76 (69.1) 27.0 (17.5)
Non-responder (n = 110)
HBeAg loss
© 2013 The Japan Society of Hepatology 0.250
0.250
0.217
0.037
0.137
0.077
0.432
0.362 0.402
0.119
P
1 12 85 0.071
1 12 85 0.071
4 51 43 0.699
22 23 53 0.658
52 19
11 (11.2) 87 (88.8)
6 (6.1) 68 (69.4) 24 (24.5)
56 42
25 (25.5) 73 (74.5) 26.2 (17.2)
Non-responder (n = 98)
0 2 44 0.022
0 2 44 0.022
2 14 30 0.804
5 6 35 0.826
20 9
9 (19.6) 37 (80.4)
3 (6.5) 22 (47.8) 21 (45.7)
25 21
15 (32.6) 31 (67.4) 27.6 (19.1)
Responder (n = 46)
Anti-HBe seroconversion
0.063
0.063
0.055
0.003
0.668
0.187
0.758
0.326 0.753
0.379
P
0 7 52 0.059
0 7 52 0.059
2 35 22 0.669
10 19 30 0.754
35 8
9 (15.3) 50 (84.7)
6 (10.2) 36 (61.0) 17 (28.8)
30 29
14 (23.7) 45 (76.3) 26.3 (17.8)
5 ULN (>200 IU/L) Baseline HBV DNA level 200 IU/L) Baseline HBV DNA level 2-times upper limit of normal), a lower serum HBV DNA level (
Hepatology Research 2014
doi: 10.1111/hepr.12284
Original Article
Effect of HLA-DP and IL28B gene polymorphisms on response to interferon treatment in hepatitis B e-antigen seropositive chronic hepatitis B patients Lin Cheng,1,2 Xiaowen Sun,1,2 Shun Tan,1,2 Wenting Tan,1,2 Yunjie Dan,1,2 Yi Zhou,1,2 Qing Mao1,2 and Guohong Deng1,2,3 1 Department of Infectious Diseases, Southwest Hospital, 3Institute of Immunology, Third Military Medical University, and 2Chongqing Key Laboratory of Infectious Diseases, Chongqing, China
Aim: The reason why the majority of chronic hepatitis B (CHB) patients do not respond to conventional interferon (IFN)-α or pegylated interferon (PEG IFN) treatment has not been formally demonstrated. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) and response to IFN-α or PEG IFN therapy in Chinese patients with CHB. Methods: Four SNPs among the HLA-DPA1, HLA-DPB1 (rs3077 and rs9277535) and IL28B (rs12979860 and rs8099917) regions were genotyped using the MGB-TaqMan SNP genotyping assay in 144 hepatitis B e-antigen (HBeAg) seropositive CHB patients who had received 6–12 months IFN-α or PEG IFN treatment. Patients were classified as responders who achieved any of the four targets: (i) the loss of HBeAg; (ii) anti-HBe seroconversion; (iii) suppression of hepatitis B virus (HBV) DNA level to below 3 log of baseline; and (iv) alanine aminotransferase normalization.
INTRODUCTION
H
EPATITIS B IS a viral infection that attacks the liver and can cause chronic disease, an estimated 2 billion people worldwide have been infected with the hepatitis B virus (HBV) and more than 240 million have chronic (long-term) liver infections. Chronic infection with HBV is a key cause of severe hepatitis B, liver cirrhosis and hepatocellular carcinoma (HCC), which
Correspondence: Dr Guohong Deng, Department of Infectious Diseases, Southwest Hospital, and Institute of Immunology, Third Military Medical University, Chongqing, 400038, China. Email: [email protected] Received 23 September 2013; revision 5 November 2013; accepted 26 November 2013.
© 2013 The Japan Society of Hepatology
Results: By multivariate analysis at 6 months of therapy and 6 months post-therapy, the results showed that rs3077-GG genotype was independently associated with higher HBeAg loss rate and anti-HBe seroconversion rate, and rs9277535-GG genotype was independently associated with decline of HBV DNA level. However, we did not observe the significant association between SNP near IL28B and the response to IFN-α or PEG IFN treatment.
Conclusion: This study suggested that HLA-DPA1 and HLADPB1 variants were significantly associated with HBeAg loss, anti-HBe seroconversion and HBV DNA level suppression in HBeAg seropositive CHB patients who received IFN-α or PEG IFN treatment. Key words: hepatitis B virus, HLA-DP, IL28B, interferon, single nucleotide polymorphisms
leads to high mortality.1 At present, conventional interferon (IFN)-α, pegylated interferon (PEG IFN) and nucleoside analogs (NUC) have been approved for the treatment of chronic HBV infection.2 Compared with NUC, IFN-α or PEG IFN treatment remains an attractive anti-HBV strategy because it provides a lower rate of relapse and can achieve HBV surface antigen (HBsAg) clearance.3,4 However, IFN-α- or PEG IFN-based therapy is modestly effective in hepatitis B e-antigen (HBeAg) loss or seroconversion in HBeAg positive patients; thus, restricted efficacy in only a proportion of patients (15– 41%) who show a response.5 Furthermore, IFN-α or PEG IFN can cause several side-effects during treatment,6 and also there are significant costs. Selection of patients with the highest probability of response for optimal use of this agent in clinical practice is essential.
1
2 L. Cheng et al.
There have been many attempts to identify pretreatment predictors of a response, resulting in the identification of high alanine aminotransferase (ALT) levels, low HBV DNA and virus genotype as significant predictors.3,4 However, all these markers are quite weak predictors of response at the individual level. Recently, a genome-wide association study identified single nucleotide polymorphisms (SNPs) located within the human leukocyte antigen (HLA) class II genes HLA-DPA1 and HLA-DPB1 to be associated with chronic hepatitis B (CHB).7 Replication studies performed on two of these SNPs (rs3077 and rs9277535) confirmed and strengthened results from the genome-wide association studies.8–10 Class II HLA genes encode proteins expressed on the surface of antigen-presenting cells such as macrophages, dendritic cells and B cells, and thereby have a critical role in presentation of antigens to CD4+ T-helper lymphocytes. HLA genes have many structural variants that have been linked to immune response to infectious agents,11 whether class II HLA gene polymorphisms associated with response to IFN-α- or PEG IFN-based treatment in CHB patients needs further investigation. In addition, the HCV field has been revolutionized by the discovery that IL28B polymorphisms can predict a sustained virological response to PEG IFN-based regimens in patients infected with HCV12–15 lately. Despite differences between HCV and HBV, investigators were tempted to test whether IL28B polymorphisms could also predict response to IFN-α- or PEG IFN-based treatment in HBV patients. Currently, data on IL28B polymorphisms and response to IFN-α or PEG IFN in HBV are scarce and conflicting,16–20 study of the relationship between IL28B polymorphisms and response to IFN-αor PEG IFN-based therapy in CHB patients in Chinese would be meaningful.
METHODS
Hepatology Research 2014
hepatitis C or D virus or HIV, association with other severe underlying disease were excluded.
Definitions of treatment responses The study had four predetermined primary measures of efficacy assessed at 6 months of therapy and 6 months post-therapy as follows; (i) the loss of HBeAg; (ii) antiHBe seroconversion; (iii) decline of HBV DNA level to below 3 log of baseline; and (iv) ALT normalization.5 Patients were classified as responders who achieved any of the four targets. Conversely, patients were classified as non-responders who did not.
Serum assays Blood samples were obtained from 144 persistent chronic HBV carriers (104 males and 40 females), 81 patients were treated with PEG IFN and 63 with IFN-α. HBV markers including HBeAg and anti-HBe antibody were tested by the automatic electrochemiluminescence immunoassay analyzer at baseline, 3 months and 6 months of therapy, and 3 months and 6 months off therapy. Serum HBV DNA load was measured by the LightCycler48 Real-time PCR instrument (Roche, Basel, Switzerland), and plasma ALT was examined by Hitachi 7060-010 automatic biochemistry analyzer (Hitachi, Tokyo, Japan).
Genotyping Genomic DNA from patients was extracted from peripheral blood using standard methods. MGB-TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were used for the detection of the referenced SNPs in HLA-DP (rs3077 and rs9277535) and near the IL28B gene (rs12979860 and rs8099917) on the chromosome.22 For allelic discrimination, genotyping of each sample was automatically attributed by the Roch 480II system (Roche).
Patients
P
ATIENTS WITH CHB who had received IFNα or Peg-IFN treatment for 6–12 months were recruited between December 2009 and November 2012 at the Department of Infectious Disease, Southwest Hospital, Chongqing, China. All patients were positive for HBsAg and HBeAg, and none of them had received standard IFN before. According to the recommendation of the Asia–Pacific consensus statement on the management of CHB, most of our patients received IFN-α or PEG IFN treatment for 6 months and only 11 patients received IFN-α or PEG IFN for 12 months.21 Cirrhosis, hepatic carcinoma, autoimmune hepatitis, co-infection with
© 2013 The Japan Society of Hepatology
Statistical analysis Statistical analysis was performed using SPSS version 18.0 software (SPSS, Chicago, IL, USA). The χ2-test was performed to examine the differences of baseline factors and the allele frequency between groups. Binary logistic regression analysis was performed to adjust risk factors such as sex, age, IFN type, baseline ALT level, HBV DNA level and HBV genotype. The association between genotyped polymorphisms and responses was estimated by P-values, odds ratios (OR) and 95% confidence intervals (95% CI), and P < 0.05 in a two-sided test was considered statistically significant.
Hepatology Research 2014
RESULTS
T
HE DEMOGRAPHIC DATA of the 144 HBeAg positive CHB patients are shown in Table 1. The overall response rates of HBsAg loss, HBeAg loss, anti-HBe seroconversion, decline of HBV DNA level to below 3 log of baseline and ALT normalization were 4.2%, 23.6%, 31.9%, 59.0% and 34.7% at 6 months of therapy, and 4.2%, 34.7%, 34.7%, 67.4% and 47.2% at 6 months off therapy, respectively. At 6 months of therapy and 6 months post-therapy, the differences of baseline factors between groups including sex, mean age, IFN type, baseline ALT level, baseline HBV DNA level, HBV genotype and the allele frequency for the four SNP were all analyzed by χ2-tests, with the results shown in Table 2 and Table 3. For the loss of HBeAg, the frequency of G allele of rs3077 was significantly higher in responders than in non-
HLA-DP, IL28B gene polymorphisms and IFN 3
responders (80.9% vs 68.8%, P = 0.037; 82.0% vs 65.4%, P = 0.002). For anti-HBe seroconversion, the G allele frequency of rs3077 was significantly higher in responders than in non-responders (82.6% vs 65.8%, P = 0.003; 81.0% vs 66.0%, P = 0.006). For HBV DNA suppression, the frequency of G allele of rs9277535 was significantly higher in responders than in nonresponders (77.6% vs 66.9%, P = 0.045; 77.8% vs 63.8%, P = 0.013). For ALT normalization at 6 months off therapy, the frequencies of rs12979860 C allele and rs8099917 T allele were significantly higher in responders than in non-responders (both P = 0.014). The multivariate analysis enrolled the baseline factors with P < 0.5 in the prior logistic regression, including sex, age, IFN type, baseline ALT level and HBV DNA level, as shown in Table 4. At 6 months of therapy and 6 months post-therapy, the results showed that rs3077-GG genotype was independently associated with
Table 1 Distribution of selected characteristics in chronic hepatitis B patients treated with conventional IFN-α or PEG IFN PEG IFN (n = 81) Sex Female, n (%) Male, n (%) Age Mean, years (1SD) Median, years (range) Pre-therapy ALT level Mean, IU/L (1SD) 1–2 × ULN (40–80 IU/L), n (%) 2–5 × ULN (80–200 IU/L), n (%) >5 ULN (>200 IU/L), n (%) Serum HBV DNA level Mean, log IU/mL (1SD) Median, log IU/mL (range) HBV genotype B, n (%) C, n (%) 6 months of therapy HBsAg loss, n (%) HBeAg loss, n (%) Anti-HBe seroconversion, n (%) HBV DNA decline 33 log, n (%) ALT normalization, n (%) 6 months off therapy HBsAg loss, n (%) HBeAg loss, n (%) Anti-HBe seroconversion, n (%) HBV DNA decline 33 log, n (%) ALT normalization, n (%)
IFN-α (n = 63)
25 (30.9) 56 (69.1)
15 (23.8) 48 (76.2)
27.8 (17.7) 26 (16–56)
25.2 (17.8) 24 (4–41)
190.5 (1121.7) 6 (7.4) 48 (59.3) 27 (33.3)
170.7 (193.1) 3 (4.8) 42 (66.7) 18 (28.6)
7.6 (10.8) 7.3 (5.0–8.6)
7.8 (10.1) 7.3 (4.1–8.9)
39 (48.1) 19 (23.5)
33 (52.4) 9 (14.3)
1 (1.2) 17 (21.0) 25 (30.9) 51 (63.0) 28 (34.6)
5 (7.9) 17 (27.0) 21 (33.3) 34 (54.0) 22 (34.9)
1 (1.2) 27 (33.3) 25 (30.9) 61 (75.3) 41 (50.6)
5 (7.9) 23 (36.5) 25 (39.7) 36 (57.1) 27 (42.9)
ALT, alanine aminotransferase; HBeAg, hepatitis B e-antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN-α, conventional interferon α; PEG IFN, pegylated interferon; SD, standard deviation; ULN, upper limit of normal.
© 2013 The Japan Society of Hepatology
17 17 1 (2.9) 20 (58.8) 13 (38.3) 8 (23.5) 26 (76.5) 13 9 4 5 25 0.809 2 11 21 0.779 0 2 32 0.029 0 2 32 0.029
8 (7.3) 70 (63.6) 32 (29.1) 12 (10.9) 98 (89.1) 59 19 23 24 63 0.688 4 54 52 0.718 1 12 97 0.064 1 12 97 0.064
6 (17.6) 28 (82.4) 25.6 (18.9)
Responder (n = 34)
64 46
34 (30.9) 76 (69.1) 27.0 (17.5)
Non-responder (n = 110)
HBeAg loss
© 2013 The Japan Society of Hepatology 0.250
0.250
0.217
0.037
0.137
0.077
0.432
0.362 0.402
0.119
P
1 12 85 0.071
1 12 85 0.071
4 51 43 0.699
22 23 53 0.658
52 19
11 (11.2) 87 (88.8)
6 (6.1) 68 (69.4) 24 (24.5)
56 42
25 (25.5) 73 (74.5) 26.2 (17.2)
Non-responder (n = 98)
0 2 44 0.022
0 2 44 0.022
2 14 30 0.804
5 6 35 0.826
20 9
9 (19.6) 37 (80.4)
3 (6.5) 22 (47.8) 21 (45.7)
25 21
15 (32.6) 31 (67.4) 27.6 (19.1)
Responder (n = 46)
Anti-HBe seroconversion
0.063
0.063
0.055
0.003
0.668
0.187
0.758
0.326 0.753
0.379
P
0 7 52 0.059
0 7 52 0.059
2 35 22 0.669
10 19 30 0.754
35 8
9 (15.3) 50 (84.7)
6 (10.2) 36 (61.0) 17 (28.8)
30 29
14 (23.7) 45 (76.3) 26.3 (17.8)
5 ULN (>200 IU/L) Baseline HBV DNA level 200 IU/L) Baseline HBV DNA level 2-times upper limit of normal), a lower serum HBV DNA level (
