Scandinavian Journal of Gastroenterology. 2015; Early Online, 1–8
ORIGINAL ARTICLE
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 04/23/15 For personal use only.
Natural history of chronic hepatitis B virus infection in childhood and efficacy of interferon therapy TOMOKO TAKANO1, HITOSHI TAJIRI1, YURI ETANI2, YOKO MIYOSHI3, YASUHITO TANAKA4 & STEPHEN BROOKS5 1
Department of Pediatrics, Osaka General Medical Center, Osaka, Japan, 2Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan, 3Department of Pediatrics, Osaka University Hospital, Suita, Japan, 4 Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, and 5Department of Microbiology/Immunology, State University of New York, Buffalo, NY, USA
Abstract Objectives. In short-term observations, interferon (IFN) therapy has been shown to be effective in producing both biochemical and virological responses in children with chronic hepatitis B virus (HBV) infection. However, in long-term follow up, no studies have shown a clear advantage of IFN therapy during childhood. We conducted a retrospective study on the sustained effect of IFN therapy among a Japanese pediatric population. Methods and subjects. A retrospective study was performed on 155 children with chronic HBV infection who were followed in two affiliated hospitals during the period from 1986 to 2013. Results. The 155 patients comprised 97 males and 58 female. Infection route was maternal transmission in 96/ 155 patients. HBV genotype was A in 17, B in 6, and C in 51 patients. IFN therapy was performed in 48 patients. One year after the completion of IFN therapy, normalization of alanine aminotransferase (ALT) and lower viral levels (1 year. The subjects were retrospectively reviewed using medical records. Chronic HBV infection was defined as being present when the
HBsAg was persistently positive for at least 6 months. There are no children with coinfection with hepatitis C virus and other potential causes of liver damage. To qualify the infection route, MTCT was defined as the route when the mother was diagnosed with HBV infection before or during pregnancy, and her child was diagnosed with hepatitis B within 6 months after birth. For infection during early childhood, father-tochild transmission was regarded as the route when the father was an HBV carrier, and other routes of familial transmission were considered as being present when other family members were HBV carriers. When there were no HBV carriers in the family, other routes of horizontal transmission were considered to be present. The normal range of serum ALT was 60 U/ml, according to the definition of Jonas et al. [13]. The following phase classification [14] was adopted: immune tolerant (HBsAg and HBeAg detectable, ALT normal), HBeAg-positive immune active (HBsAg and HBeAg detectable, ALT persistently elevated), HBeAg-negative immune active (HBsAg detectable, HBeAg undetectable, ALT persistently elevated), inactive carrier (HBeAg undetectable, anti-HBe antibodies present, ALT normal) [15]. The patients were divided into two groups according to mode of transmission, maternal or non-maternal. For comparison between the IFN therapy and untreated groups, an untreated group was defined as children with hepatitis persisting for ‡6 months whose clinical course was observed without treatment. IFN therapy Prior to IFN therapy, a liver biopsy was taken and scored for hepatitis activity (grading A0–A3) and fibrotic changes (staging F0–F4) according to the New Inuyama classification [16]. The indication of IFN therapy for children with chronic hepatitis B was decided according to the following conditions: (i) elevation of ALT levels (‡60 U/ml) for ‡6 months; and (ii) pathological findings of chronic hepatitis that included grading A2 and A3, or staging F2 and F3. Criteria for exclusion from IFN therapy were liver cirrhosis (stage F4), underlying systemic diseases, metabolic liver disorders, and severe neurological impairment, and none of the present patients met this exclusion criteria. Before IFN therapy, all patients were clinically asymptomatic, and had wellcompensated liver function with normal serum levels of bilirubin and albumin and a normal prothrombin coagulation time. IFN therapy was performed in 48 patients between 1989 and 2010. In Japan, IFN therapy was approved
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 04/23/15 For personal use only.
Chronic hepatitis B virus infection for children for use in 4 weeks from 1986 to 1991, for 12 weeks from 1991 and 2000, and for 24 weeks after 2000. The amount of lymphoblastoid a-IFN (OIF: Otsuka Pharmaceuticals Co. Ltd, Tokyo, Japan, Sumiferon: Dainippon Sumitomo Pharma, Osaka, Japan) was limited up to 100,000 U/kg/dose during these periods. The durations and regimens of treatment were as follows: 4 weeks (7 patients; daily for 4 weeks, 28 doses in total), 12 weeks (27 patients; 3 times a week, 36 doses in total), and 24 weeks (12 patients; 3 times a week, 72 doses in total). In two patients with severe fibrosis (F3), IFN therapy was extended to 52 weeks. Statistical analysis Data are expressed as a median with a range. Differences between groups were examined for statistical significance using the Fisher’s exact probability test and Mann–Whitney U test, where appropriate. The HBeAg seroconversion rate, the ALT normalization rate, and the rate of achieving a low HBV-DNA level were compared between the IFN therapy and untreated groups using the Cox’s proportional hazard analysis and p-values were calculated using the Cox–Mantel logrank test (the SPSS V.20 statistical package software). All statistical analyses were based on two-sided hypothesis tests with a significance level of p < 0.05. Results The 155 patients comprised 97 boys and 58 girls. The median age at diagnosis was 3.9 years, and the median follow-up period was 8 years (Table I). The infection route was MTCT in 62% of the patients, followed by father-to-child transmission and blood transfusion. HBV genotype, which was determined in 84 of 155 patients, was type C in 73% of the 84 patients, followed by types A and B. During the follow-up period, an elevation in ALT levels was observed in 144 patients, and hepatitis persisted for ‡6 months in 114 patients with the median duration of hepatitis of 3.0 years. First-line treatment was performed in 49 of those 114 patients with chronic hepatitis. IFN was adopted in 48 patients and lamivudine in 1 patient. The clinical phase at the last visit was: immune tolerant in 20%, HBeAg-positive immune active in 18%, HBeAg-negative immune active in 19%, and inactive carriers in 43%. The HBV-DNA level at the last visit was £104 copies/ml (low viral load) in 47%. HCC developed in three patients. The demographic features of children with chronic HBV infection were compared between 96 patients with MTCT and 59 with non-maternal transmission (Table II). There was no difference in the male–to-
3
Table I. Clinical profiles of 155 patients with hepatitis B virus infection. n (%) Sex (male/female) Age at diagnosis Duration of follow-up (years) Route of infection Mather to child Father to child Blood transfusion Not identified Genotype A B C Children with persistently elevated serum ALT £6 month >6 month None Duration of hepatitis Treatment IFN Lamivudine No treatment Clinical phase at last visit Immune tolerant HBeAg-positive immune active HBeAg-negative immune active Inactive carrier Viral loads at last visit HBV-DNA >104 copies/ml HBV-DNA £104 copies/ml Hepatocellular carcinoma
97/58 3.9 (0–15) 8 (1–33) 96 (62) 14 (9) 5 (3) 40 (26) 17/84 (20) 6/84 (7) 61/84 (73) 114 (74) 30 (19) 11 (7) 3.0 (0.2–16) 48 (31) 1 (1) 106 (68) 32 28 29 66
(20) (18) (19) (43)
44/92 (47) 48/92 (53) 3
Abbreviations: ALT = Alanine aminotransferase; HBeAg = Hepatitis B e-antigen; HBV = Hepatitis B virus; IFN = Interferon.
female ratio and follow-up period between the two groups. The MTCT group was significantly younger at the age of diagnosis (p < 0.001). Genotype C was more frequently observed in the MTCT group, whereas not only genotype C but also genotype A was observed in the non-maternal transmission group. An elevation in ALT level was noted in 96% of patients in the non-maternal transmission group and in 75% of those in the MTCT group (p < 0.001). The duration of hepatitis was not different between the two groups. At the last visit, the proportion of patients in the immune-tolerant phase was higher in the MTCT group than in the nonmaternal transmission group (p < 0.001). IFN therapy was performed in 48 patients comprising 36 boys and 12 girls with the median age of 10.5 years. Of the 48 patients, 43 were HBeAg-positive and 5 were HBeAg-negative prior to IFN therapy. Among the 48 patients, HBeAg seroconversion was confirmed in 79%, serum ALT levels were normalized in 90%, and viral loads were decreased to 104 copies/ml £104 copies/ml Hepatocellular carcinoma
Maternal infection (n = 96)
Non-maternal infection (n = 59)
p-value
56/40 1.0 (0–14) 6.0 (1–27)
41/18 6.9 (0.2–15) 4.85 (1–33)
0.110 < 0.001 0.859
0 4/45 (9) 41/45 (91) 72 (75) 3.0 (0.25–16)
17/39 (44) 2/39 (5) 20/39 (51) 57 (96) 3.0 (0.2–12)
< 0.001 0.681 < 0.001 < 0.001 0.890
25 36 17 17
2 (3) 35 (59) 13 (22) 8 (14)
< 0.001 0.006 0.323 0.328
7/38 (18) 31/38 (82) 2
1.000
(26) (38) (18) (18)
11/62 (18) 51/62 (82) 1
Abbreviations: ALT = Alanine aminotransferase; HBeAg = Hepatitis B e-antigen; HBV = Hepatitis B virus.
The effects of IFN therapy were evaluated by comparing the 43 IFN-treated patients who were in the HBeAg-positive hepatitis phase (IFN group) with the 66 HBeAg-positive patients with hepatitis persisting
for ‡6 months and whose clinical course was observed without treatment (untreated group) (Table III). There was no difference in the age at diagnosis of HBV infection, sex, duration of follow up, infection
Table III. Comparison of characteristics of HBeAg-positive children with IFN treatment and those without treatment.
Age at diagnosis (years) Sex (male/female) Duration of follow up (years) Route of infection Mather to child Father to child Transfusion Not identified Genotype A B C Baseline ALT levels (IU/ml) Peak ALT levels (IU/ml) Baseline HBV-DNA levels (log copies/ml) Low viral load at baseline* Duration of hepatitis (years) HBeAg/Ab seroconversion at 1 year Clinical phase at last visit Immune tolerant (HBeAg-positive) HBeAg-positive immune active HBeAg-negative immune active Inactive carrier (HBeAg-negative) HBeAg/Ab seroconversion at last visit Age at seroconversion (years) ALT normalization at last visit Low viral load at last visit* HBsAg loss at last visit
IFN treatment (n = 43)
Without treatment (n = 6)
p-value
4.0 (0–15) 31/12 6.7 (3–22)
3.0 (0–14.9) 39/27 6.0 (2–19)
0.232 0.220 0.232 0.101
21 (49) 6 (14) 2 (5) 14 (33)
43 (65) 2 (3) 2 (3) 19 (29)
11/39 (28) 2/39 (5) 26/39 (67) 156 (66–591) 275 (83–855) 8.2 (0.7) 8 (18) 4.0 (0.5–16) 28 (65)
5/29 (17) 2/29 (7) 22/29 (76) 106 (54–506) 149 (72–1017) 8.3 (1.3) 14 (21) 3.0 (0.6–12) 17 (25)
0.624 0.432 0.299 0.810 0.029
ORIGINAL ARTICLE
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 04/23/15 For personal use only.
Natural history of chronic hepatitis B virus infection in childhood and efficacy of interferon therapy TOMOKO TAKANO1, HITOSHI TAJIRI1, YURI ETANI2, YOKO MIYOSHI3, YASUHITO TANAKA4 & STEPHEN BROOKS5 1
Department of Pediatrics, Osaka General Medical Center, Osaka, Japan, 2Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan, 3Department of Pediatrics, Osaka University Hospital, Suita, Japan, 4 Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, and 5Department of Microbiology/Immunology, State University of New York, Buffalo, NY, USA
Abstract Objectives. In short-term observations, interferon (IFN) therapy has been shown to be effective in producing both biochemical and virological responses in children with chronic hepatitis B virus (HBV) infection. However, in long-term follow up, no studies have shown a clear advantage of IFN therapy during childhood. We conducted a retrospective study on the sustained effect of IFN therapy among a Japanese pediatric population. Methods and subjects. A retrospective study was performed on 155 children with chronic HBV infection who were followed in two affiliated hospitals during the period from 1986 to 2013. Results. The 155 patients comprised 97 males and 58 female. Infection route was maternal transmission in 96/ 155 patients. HBV genotype was A in 17, B in 6, and C in 51 patients. IFN therapy was performed in 48 patients. One year after the completion of IFN therapy, normalization of alanine aminotransferase (ALT) and lower viral levels (1 year. The subjects were retrospectively reviewed using medical records. Chronic HBV infection was defined as being present when the
HBsAg was persistently positive for at least 6 months. There are no children with coinfection with hepatitis C virus and other potential causes of liver damage. To qualify the infection route, MTCT was defined as the route when the mother was diagnosed with HBV infection before or during pregnancy, and her child was diagnosed with hepatitis B within 6 months after birth. For infection during early childhood, father-tochild transmission was regarded as the route when the father was an HBV carrier, and other routes of familial transmission were considered as being present when other family members were HBV carriers. When there were no HBV carriers in the family, other routes of horizontal transmission were considered to be present. The normal range of serum ALT was 60 U/ml, according to the definition of Jonas et al. [13]. The following phase classification [14] was adopted: immune tolerant (HBsAg and HBeAg detectable, ALT normal), HBeAg-positive immune active (HBsAg and HBeAg detectable, ALT persistently elevated), HBeAg-negative immune active (HBsAg detectable, HBeAg undetectable, ALT persistently elevated), inactive carrier (HBeAg undetectable, anti-HBe antibodies present, ALT normal) [15]. The patients were divided into two groups according to mode of transmission, maternal or non-maternal. For comparison between the IFN therapy and untreated groups, an untreated group was defined as children with hepatitis persisting for ‡6 months whose clinical course was observed without treatment. IFN therapy Prior to IFN therapy, a liver biopsy was taken and scored for hepatitis activity (grading A0–A3) and fibrotic changes (staging F0–F4) according to the New Inuyama classification [16]. The indication of IFN therapy for children with chronic hepatitis B was decided according to the following conditions: (i) elevation of ALT levels (‡60 U/ml) for ‡6 months; and (ii) pathological findings of chronic hepatitis that included grading A2 and A3, or staging F2 and F3. Criteria for exclusion from IFN therapy were liver cirrhosis (stage F4), underlying systemic diseases, metabolic liver disorders, and severe neurological impairment, and none of the present patients met this exclusion criteria. Before IFN therapy, all patients were clinically asymptomatic, and had wellcompensated liver function with normal serum levels of bilirubin and albumin and a normal prothrombin coagulation time. IFN therapy was performed in 48 patients between 1989 and 2010. In Japan, IFN therapy was approved
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 04/23/15 For personal use only.
Chronic hepatitis B virus infection for children for use in 4 weeks from 1986 to 1991, for 12 weeks from 1991 and 2000, and for 24 weeks after 2000. The amount of lymphoblastoid a-IFN (OIF: Otsuka Pharmaceuticals Co. Ltd, Tokyo, Japan, Sumiferon: Dainippon Sumitomo Pharma, Osaka, Japan) was limited up to 100,000 U/kg/dose during these periods. The durations and regimens of treatment were as follows: 4 weeks (7 patients; daily for 4 weeks, 28 doses in total), 12 weeks (27 patients; 3 times a week, 36 doses in total), and 24 weeks (12 patients; 3 times a week, 72 doses in total). In two patients with severe fibrosis (F3), IFN therapy was extended to 52 weeks. Statistical analysis Data are expressed as a median with a range. Differences between groups were examined for statistical significance using the Fisher’s exact probability test and Mann–Whitney U test, where appropriate. The HBeAg seroconversion rate, the ALT normalization rate, and the rate of achieving a low HBV-DNA level were compared between the IFN therapy and untreated groups using the Cox’s proportional hazard analysis and p-values were calculated using the Cox–Mantel logrank test (the SPSS V.20 statistical package software). All statistical analyses were based on two-sided hypothesis tests with a significance level of p < 0.05. Results The 155 patients comprised 97 boys and 58 girls. The median age at diagnosis was 3.9 years, and the median follow-up period was 8 years (Table I). The infection route was MTCT in 62% of the patients, followed by father-to-child transmission and blood transfusion. HBV genotype, which was determined in 84 of 155 patients, was type C in 73% of the 84 patients, followed by types A and B. During the follow-up period, an elevation in ALT levels was observed in 144 patients, and hepatitis persisted for ‡6 months in 114 patients with the median duration of hepatitis of 3.0 years. First-line treatment was performed in 49 of those 114 patients with chronic hepatitis. IFN was adopted in 48 patients and lamivudine in 1 patient. The clinical phase at the last visit was: immune tolerant in 20%, HBeAg-positive immune active in 18%, HBeAg-negative immune active in 19%, and inactive carriers in 43%. The HBV-DNA level at the last visit was £104 copies/ml (low viral load) in 47%. HCC developed in three patients. The demographic features of children with chronic HBV infection were compared between 96 patients with MTCT and 59 with non-maternal transmission (Table II). There was no difference in the male–to-
3
Table I. Clinical profiles of 155 patients with hepatitis B virus infection. n (%) Sex (male/female) Age at diagnosis Duration of follow-up (years) Route of infection Mather to child Father to child Blood transfusion Not identified Genotype A B C Children with persistently elevated serum ALT £6 month >6 month None Duration of hepatitis Treatment IFN Lamivudine No treatment Clinical phase at last visit Immune tolerant HBeAg-positive immune active HBeAg-negative immune active Inactive carrier Viral loads at last visit HBV-DNA >104 copies/ml HBV-DNA £104 copies/ml Hepatocellular carcinoma
97/58 3.9 (0–15) 8 (1–33) 96 (62) 14 (9) 5 (3) 40 (26) 17/84 (20) 6/84 (7) 61/84 (73) 114 (74) 30 (19) 11 (7) 3.0 (0.2–16) 48 (31) 1 (1) 106 (68) 32 28 29 66
(20) (18) (19) (43)
44/92 (47) 48/92 (53) 3
Abbreviations: ALT = Alanine aminotransferase; HBeAg = Hepatitis B e-antigen; HBV = Hepatitis B virus; IFN = Interferon.
female ratio and follow-up period between the two groups. The MTCT group was significantly younger at the age of diagnosis (p < 0.001). Genotype C was more frequently observed in the MTCT group, whereas not only genotype C but also genotype A was observed in the non-maternal transmission group. An elevation in ALT level was noted in 96% of patients in the non-maternal transmission group and in 75% of those in the MTCT group (p < 0.001). The duration of hepatitis was not different between the two groups. At the last visit, the proportion of patients in the immune-tolerant phase was higher in the MTCT group than in the nonmaternal transmission group (p < 0.001). IFN therapy was performed in 48 patients comprising 36 boys and 12 girls with the median age of 10.5 years. Of the 48 patients, 43 were HBeAg-positive and 5 were HBeAg-negative prior to IFN therapy. Among the 48 patients, HBeAg seroconversion was confirmed in 79%, serum ALT levels were normalized in 90%, and viral loads were decreased to 104 copies/ml £104 copies/ml Hepatocellular carcinoma
Maternal infection (n = 96)
Non-maternal infection (n = 59)
p-value
56/40 1.0 (0–14) 6.0 (1–27)
41/18 6.9 (0.2–15) 4.85 (1–33)
0.110 < 0.001 0.859
0 4/45 (9) 41/45 (91) 72 (75) 3.0 (0.25–16)
17/39 (44) 2/39 (5) 20/39 (51) 57 (96) 3.0 (0.2–12)
< 0.001 0.681 < 0.001 < 0.001 0.890
25 36 17 17
2 (3) 35 (59) 13 (22) 8 (14)
< 0.001 0.006 0.323 0.328
7/38 (18) 31/38 (82) 2
1.000
(26) (38) (18) (18)
11/62 (18) 51/62 (82) 1
Abbreviations: ALT = Alanine aminotransferase; HBeAg = Hepatitis B e-antigen; HBV = Hepatitis B virus.
The effects of IFN therapy were evaluated by comparing the 43 IFN-treated patients who were in the HBeAg-positive hepatitis phase (IFN group) with the 66 HBeAg-positive patients with hepatitis persisting
for ‡6 months and whose clinical course was observed without treatment (untreated group) (Table III). There was no difference in the age at diagnosis of HBV infection, sex, duration of follow up, infection
Table III. Comparison of characteristics of HBeAg-positive children with IFN treatment and those without treatment.
Age at diagnosis (years) Sex (male/female) Duration of follow up (years) Route of infection Mather to child Father to child Transfusion Not identified Genotype A B C Baseline ALT levels (IU/ml) Peak ALT levels (IU/ml) Baseline HBV-DNA levels (log copies/ml) Low viral load at baseline* Duration of hepatitis (years) HBeAg/Ab seroconversion at 1 year Clinical phase at last visit Immune tolerant (HBeAg-positive) HBeAg-positive immune active HBeAg-negative immune active Inactive carrier (HBeAg-negative) HBeAg/Ab seroconversion at last visit Age at seroconversion (years) ALT normalization at last visit Low viral load at last visit* HBsAg loss at last visit
IFN treatment (n = 43)
Without treatment (n = 6)
p-value
4.0 (0–15) 31/12 6.7 (3–22)
3.0 (0–14.9) 39/27 6.0 (2–19)
0.232 0.220 0.232 0.101
21 (49) 6 (14) 2 (5) 14 (33)
43 (65) 2 (3) 2 (3) 19 (29)
11/39 (28) 2/39 (5) 26/39 (67) 156 (66–591) 275 (83–855) 8.2 (0.7) 8 (18) 4.0 (0.5–16) 28 (65)
5/29 (17) 2/29 (7) 22/29 (76) 106 (54–506) 149 (72–1017) 8.3 (1.3) 14 (21) 3.0 (0.6–12) 17 (25)
0.624 0.432 0.299 0.810 0.029
