Chronic Hepatitis B Virus Infection In Children Research Articles

Treatment of hepatitis B virus infection in children and adolescents.

Hepatitis B virus (HBV) infection is one of the main causes of morbidity and mortality worldwide. Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by a high viral replication and a low-inflammation phase of infection, with normal or only slightly raised aminotransferases. Although a conservative approach in children is usually recommended, different therapies exist and different therapeutic approaches are possible. The main goals of antiviral treatment for children with chronic HBV infection are to suppress viral replication and to warn the disease progression to cirrhosis and hepatocellular carcinoma, although these complications are rare in children. Both United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) have approved interferon alfa-2b for children aged 1 year and older, pegylated interferon alfa-2a and lamivudine for children aged 3 years and older, entecavir for use in children aged 2 years and older, and adefovir for use in those 12 years of age and older. Tenofovir disoproxil fumarate is approved by EMA for children aged 2 years and older and by US-FDA for treatment in children aged 12 years and older. Finally, EMA has approved the use of tenofovir alafenamide for treatment of children aged 12 years and older or for children weighing more than 35 kg independent of age. This narrative review will provide the framework for summarizing indications to antiviral therapy in the management of chronic HBV infection in children and adolescents.

Decreased neonatal hepatitis B virus (HBV) viremia by maternal tenofovir treatment predicts reduced chronic HBV infection in children born to highly viremic mothers.

Maternal anti-viral treatment prevents mother-to-infant transmission of hepatitis B virus (HBV), but the role of neonatal viremia on subsequent HBV infection is not clear. To investigate the effect of maternal anti-viral treatment on neonatal serum HBV DNA and hepatitis B surface antigen (HBsAg) in infants born to highly viremic mothers and the roles of neonatal markers in predicting chronic HBV infection in children. Serum HBV DNA and HBsAg were tested in children. Of the 201 pregnant mothers, 110 received tenofovir during the third trimester. Chronic infection in children was defined by HBsAg seropositivity at 6 or 12months lasting more than 6months. The maternal HBV viral loads from baseline to delivery were 8.25±0.48 to 4.29±0.98 log10 IU/mL; and 8.29±0.49 to 8.12±0.68 log10 IU/mL in the tenofovir and control group respectively. Of the 208 children, those in the tenofovir group had a lower rate of neonatal HBV DNA seropositivity at birth (5.22% vs 30.11%, P<0.0001) and HBsAg seropositivity at 6months (1.74% vs 11.83%, P=0.003) and 12months (1.74% vs 10.75%, P=0.007). In a first multivariate analysis, maternal HBV DNA level at delivery (odds ratio=1.70, P=0.0172) and neonatal HBsAg positivity (odds ratio=19.37, P<0.0001) were significantly associated with children's chronic HBV infection. In a second model, neonatal HBV DNA positivity was a strong independent influence variable (odds ratio=61.89, P=0.0002). Maternal tenofovir therapy decreased maternal viral load and neonatal viremia. Positive neonatal HBV DNA was highly correlated with chronic HBV infection in children. Clinical Trial Identifier: NCT01312012.

The Impact of Hepatitis B Vaccine Failure on Long-term Natural Course of Chronic Hepatitis B Virus Infection in Hepatitis B e Antigen-Seropositive Children.

Vaccine failure with chronic hepatitis B virus (HBV) infection still develops in children after universal hepatitis B immunization. This study aimed to investigate the natural course of chronic HBV infection in children with vaccine failure and compare it with that of nonvaccinated children. Three hundred fifty-six hepatitis B e antigen (HBeAg)-seropositive, hepatitis B surface antigen (HBsAg) carrier children, who were followed for at least 1 year without antiviral therapy, were enrolled. These comprised 105 vaccine failure subjects who received 3 doses of HBV vaccine in infancy and 251 nonvaccinated subjects. The clinical, serologic, and virologic features were compared between the 2 groups. The cumulative HBeAg seroconversion rate was significantly lower in the vaccine failure group than in the nonvaccinated group (30.5% vs 77.7%, P < .0001). Genotype C HBV infection was more frequent in the vaccine failure group (33.7% vs 13.4%, P < .0001), and the maternal HBsAg-positive rate was higher (97.1% vs 66.4%, P < .0001). In a multivariate analysis, vaccine failure, genotype C infection, and maternal HBsAg positivity were significantly associated with delayed HBeAg seroconversion. HBeAg-seropositive vaccine failure HBV-carrier children were associated with delayed HBeAg seroconversion during long-term follow-up, and more HBV genotype C infection and maternal HBsAg seropositivity.

Variations in IL-1R1 Gene Influence Risk for Hepatitis B Virus Infection of Children in a Han Chinese population

Background/AimsHost genetic factors play an important role in the pathogenesis of hepatitis B virus (HBV) infection. However, the role of Interleukin1Receptor, Type I (IL-1R1) gene in HBV infection and breakthrough infection in children remains unclear. The aim of this study was to investigate the association between SNPs in IL-1 family and HBV infection and breakthrough infection in children. Patients and MethodsA total of 627 Chinese children (274 HBV infected children and 353 controls) ages 6 months to 12 years were recruited from October 2013 to May 2015.Six SNPs were genotyped in IL-1R1, Interleukin-1beta (IL-1B) and Interleukin-18 (IL-18) genes. ResultsA statistically significant association was found between genotype AA in rs3917267 (IL-1R1) and HBV infection in children (OR, 1.740; 95%CI, 1.091–2.774; p=0.020), which was also found at allele A (OR, 1.316;95%CI, 1.050–1.648; p=0.017). Furthermore, rs3917267 was also significantly associated with breakthrough infection of HBV in children born of hepatitis B surface antigen (HBsAg) positive mothers (OR,3.675; 95%CI, 1.160-11.646; P=0.027). ConclusionOur study confirmed that genetic variant in IL-1R1(rs3917267) has significant association with HBV infection and HBV breakthrough infection in children, which provides new clues for the study of pathogenesis of chronic HBV infection in children.

PTU-111 A review of chronic hepatitis b virus infection in children in ireland

Introduction Although the majority of children with hepatitis B virus (HBV) infection remain asymptomatic, serious complications such as cirrhosis and hepatocellular carcinoma can occur in later life. Longterm follow up is important to identify these complications early. In Ireland, pregnant women are screened antenatally for HBV. Children born to HBV infected mothers are referred to the Rainbow Clinic. Method Data on all children with chronic HBV infection, attending the Rainbow Clinic from 2002 to 2014, were retrospectively reviewed using a standard data collection sheet. Chronic HBV infection is defined as HBsAg-positivity for greater than 6 months. Children with only one clinic visit or with HIV co-infection were excluded. Results 63 children with chronic HBV infection attended the Rainbow clinic between 2002 and 2014 (age range, 6 months-17 years).6 children were excluded (4 single clinic attendance; 2 HIV co-infection). 34 children (60%) were male. 13 children (23%) with chronic HBV were born in Ireland. The majority (44, 77%) were children immigrating to Ireland from overseas: Africa, 16; Central Asia, 14; Eastern Europe, 7; Unknown, 7. HBV was acquired vertically in 35 (61%) children and horizontally in 2. Parental HBV status was unknown in 22 children (15 adoptees).19 children had siblings with chronic HBV infection. 9 of 13 (69%) children born in Ireland received recommended prophylactic IVIG and HBV vaccine at birth. 4 (31%) received no prophylaxis. Birth details from children born outside of Ireland show suboptimal post natal prophylaxis in all: 13 of 16 received no prophylaxis and 3 received HBV vaccine alone. All 57 children had biochemistry performed twice a year. Abdominal ultrasound scans (USS) were performed in 49 children (86%).5 had abnormal USS (coarse echogenicity, 3; splenomegaly, 2). Liver biopsy was performed in 4 children with elevated ALT and high HBV VL. Biopsies showed fibrosis (3) or minimal inflammation (1). USS was normal in 3 of the 4 cases with abnormal biopsy. 3 children received antivirals (3TC) for fibrosis (2) and to reduce risk of transmission (1). Conclusion Immigration to Ireland accounts for the majority of paediatric HBV infection in this country. The majority of chronic HBV infection in children results from vertical transmission. Failure of postnatal prophylaxis remains a significant problem. Available evidence shows that 100% of foreign-born and 30% of Irish-born children with chronic HBV did not received recommended IVIG and vaccine prophylaxis. 4 children (7%) developed complications of chronic HBV. The need for improved diagnostic tools to identify children at risk of complicated HBV liver disease is again evidenced by failure of USS to identify those children with biopsy-proven abnormalities. Disclosure of interest None Declared.

Association between single-nucleotide polymorphisms and early spontaneous hepatitis B virus e antigen seroconversion in children.

BackgroundThe disease progression following hepatitis B virus (HBV) infection is associated with single-nucleotide polymorphisms (SNPs). However, the role of SNPs in chronic HBV infection in children remains unclear. Here, we investigate the association between SNPs and early spontaneous hepatitis B e antigen (HBeAg) seroconversion in children with chronic hepatitis B infection.MethodsThis was a retrospective cohort study. We genotyped seven SNPs in the following genes, interleukin (IL)-10 (rs1800871 and rs1800872), human leukocyte antigen (HLA)-DPA1 (rs3077), HLA-DPB1 (rs9277535), HLA-DQB2 (rs7453920), HLA-DQB1 (rs2856718), and IL28B (rs8099917), in patients with chronic HBV infection using PCR and sequencing. These variants were analyzed for an association with early HBeAg seroconversion in children.ResultsOf 225 Japanese patients with chronic hepatitis B virus infection (male/female: 105/120, median age at initial visit: 6 years; range 0–44 years), 52 achieved spontaneous HBeAg seroconversion at the age of 10 years or younger (G1: early seroconversion group), and 57 did not achieve spontaneous HBeAg seroconversion under the age of 20 years (G2: late or no seroconversion group). Of the seven SNPs, only the HLA-DPA1 SNP displayed a low p-value (P = 0.070), but not significant, to have early HBeAg seroconversion in the dominant model and in the allele model (P = 0.073) using the chi-square test. The association study found a low p-value, but not significant, to have early HBeAg seroconversion in the dominant model for HLA-DPA1 (genotype TC + TT vs. CC, P = 0.070, odds ratio: 2.016, 95% confidence interval: 0.940-4.323) using a logistic regression model.ConclusionAlthough the HLA-DPA1 SNP did not show a statistically significant association with early HBeAg seroconversion in this study, the HLA-DPA1 SNP might increase the likelihood of achieving early spontaneous HBeAg seroconversion in children.

Protective efficacy against chronic hepatitis B virus infection after neonatal hepatitis B vaccination in China: A summary

Transmission of hepatitis B virus (HBV) during the perinatal period and in young children has been effectively prevented in recent years, with increased rates of coverage and timely immunization of hepatitis B vaccine to neonates in mainland China. Prevalence of HBV surface antigen (HBsAg) and chronic HBV infection in children have decreased both in rural and urban areas. The incidence of hepatitis B and primary hepatocellular carcinoma has also been reduced in children and young people. The effects of immunoprotection against HBV infection were found to last for at least 20 years. The presence of immune memory was associated with titers of antibody to HBV surface antigen (anti-HBs) in young children vaccinated at an early age. Results from our recent clinical investigation suggest that a universal booster immunization is not necessary for children and teenagers after neonatal vaccination. In this review, issues arising from representative vaccination-coverage areas, including Qidong, Jiangsu Province, are also discussed. These include immunoprophylaxis failure against vertical transmission, low or no response to the vaccines, isolated anti-HBc positivity, occult HBV infection after vaccination, and the effects of vaccination on HBV genotype and mutation.

Modeling the transmission dynamics and control of hepatitis B virus in China

Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus (HBV) and is a major global health problem. HBV is the most common serious viral infection and a leading cause of death in mainland China. Around 130 million people in China are carriers of HBV, almost a third of the people infected with HBV worldwide and about 10% of the general population in the country; among them 30 million are chronically infected. Every year, 300,000 people die from HBV-related diseases in China, accounting for 40-50% of HBV-related deaths worldwide. Despite an effective vaccination program for newborn babies since the 1990s, which has reduced chronic HBV infection in children, the incidence of hepatitis B is still increasing in China. We propose a mathematical model to understand the transmission dynamics and prevalence of HBV infection in China. Based on the data reported by the Ministry of Health of China, the model provides an approximate estimate of the basic reproduction number R(0)=2.406. This indicates that hepatitis B is endemic in China and is approaching its equilibrium with the current immunization program and control measures. Although China made a great progress in increasing coverage among infants with hepatitis B vaccine, it has a long and hard battle to fight in order to significantly reduce the incidence and eventually eradicate the virus.

Source of transmission in children with chronic hepatitis B infection after the implementation of a strategy for prevention in those at high risk

In order to clarify the sources of chronic HBV (hepatitis B virus) infection in children after the implementation of an "at-risk" strategy in Japan, chronically infected children were assessed. In addition, chronically infected children born to HBsAg-negative mothers and their family members were assessed to identify the sources of HBV transmission. Fifty-seven children who tested HBsAg-positive after the initiation of a mother-to-child transmission prevention program were enrolled in this study. The full-genome HBV DNA sequence was analyzed to confirm the transmission sources. Of the 57 patients, 37 (65%) were born to HBV carrier mothers. The remaining 20 (35%) patients were born to HBsAg-negative mothers. Fourteen of these patients had HBV carrier fathers, and 2 patients, who were siblings, did not have an HBV carrier father. The remaining 4 patients had no family members with HBV infection. Phylogenetic tree analysis confirmed that father-to-child transmission and sibling-to-sibling transmission occurred in 3 families and 1 family, respectively. Although vaccine failure of mother-to-child transmission was the major cause of chronic HBV infection in children, father-to-child transmission was the second most common mode of transmission. In addition, sibling-to-sibling transmission was found. Unless at-risk individuals and groups can be accurately identified to prevent horizontal transmission, the introduction of universal vaccination is essential for achieving the elimination of HBV infection in Japan.

Management of Chronic Hepatitis B in Children

Hepatitis B virus (HBV) infection is a worldwide problem and can cause acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer. In areas of high prevalence such as in Asia, Africa, southern Europe, and Latin America, the hepatitis B surface antigen positive rate ranges from 2% to 20%.In endemic areas, HBV infection occurs mainly during infancy and early childhood. Mother-to-infant transmission accounts for approximately half of the chronic HBV infections. In contrast to infection in adults, HBV infection during early childhood results in a much higher rate of persistent infection and long-term serious complications such as liver cirrhosis and HCC.Three phases of chronic hepatitis B have been identified: the immune-tolerant phase, the immune-active phase, and the inactive hepatitis B phase. These phases of infection are characterized by variations in viral replication, hepatic inflammation, spontaneous clearance, and response to antiviral therapy.The optimal goal of antiviral therapy for chronic HBV infection is to eradicate HBV and to prevent its related liver complications. However, due to the limited effect of available therapies in viral eradication, the goal of treatment is to reduce viral replication, to minimize liver injury, and to reduce infectivity. In this review the current recommendations for monitoring and treating chronic HBV infection in children are reviewed.

Hepatitis B therapy in children

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease throughout the world, leading to cirrhosis and hepatocellular carcinoma in many individuals. Children are more likely to develop chronic HBV infection as they demonstrate greater immunotolerance to the virus, and response to therapy in children remains disappointing. Three therapeutic agents for chronic HBV infection in children have been approved in the USA, including standard IFN-α, lamivudine and adefovir. IFN-α has been the most effective (∼30% hepatitis B e antigen [HBeAg] seroconversion; 10% hepatitis B surface antigen [HBsAg] seroconversion), although benefits are primarily observed in children with alanine aminotransferase levels over two-times the upper limit of normal and must be weighed against significant side effects. Studies comparing the long-term outcome of chronic hepatitis B in children treated with IFN-α and in untreated controls show that the rate of anti-HBeAb seroconversion tends to overlap in treated and untreated patients within a few years of follow-up, suggesting that IFN-α simply accelerates a spontaneous event. Lamivudine’s virologic response rates mirror those of IFN-α (23–31% HBeAg seroconversion) with easier administration and a better safety profile but lower HBsAg seroconversion (2–3%) and high rates of drug resistance. Adefovir data show low rates of resistance and a good safety profile, but virologic response was limited to adolescent patients and was lower than that of lamivudine (16% HBeAg seroconversion; <1% HBsAg seroconversion). Entecavir and tenofovir, both approved therapies for adults with chronic HBV infection, are in trials for use in children. Future therapies will probably include these agents as well as combined therapies. Finally, watchful waiting of children is an option since current therapies are only 30% effective at best, although the long-term impact of therapy in childhood on rates of cirrhosis and hepatocellular carcinoma remains unknown.

Natural history and clinical management of chronic hepatitis B virus infection in children

Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.

Hepatitis B Virus: Something Old, Something New

Hepatitis B Virus: Something Old, Something New

Profile of chronic hepatitis B virus in children in India: Experience with 116 children

Hepatitis B virus (HBV) infection in children is mostly asymptomatic and therefore the disease burden is likely to be under appreciated. There is limited information on the profile of chronic HBV infection in children from the Indian subcontinent. In 116 (male:female 89:27) children, aged <15 years, with persistent HBsAg positivity for more than 6 months, a clinical, biochemical, virological and histological assessment was carried out. At presentation, 21.6% of children were symptomatic, with icterus in 12%. Features of decompensation such as ascites (7%) and gastrointestinal (GI) bleed (5%) were noted uncommonly. Five (4.3%) children had hepatocellular carcinoma (HCC) at presentation. Elevated alanine aminotransferase (ALT) was observed in 76% of subjects (median 61; range 14-815). A significantly higher proportion of children with hepatitis B early antigen (HbeAg) positive status had higher histological activity index (HAI) (84% vs 16%, P < 0.001) and fibrosis score (80% vs 20%, P = 0.007). A strong positive correlation was noted between aspartate aminotransferase (AST), ALT, HBV-DNA and histological severity of the disease (HAI > or =4, fibrosis > or =2). Median HBV-DNA levels were significantly higher in the HBeAg positive compared to the HBeAg negative group (25.6 vs 0.7 pg/mL, P = 0.004). Seventy-four percent of the mothers had evidence of past or present HBV infection. Majority of the children with chronic HBV infection are asymptomatic at presentation. HBeAg positive status reflects histologically more severe disease, and a higher level of HBV-DNA. Almost two-thirds of the children may have acquired their HBV infection perinataly.

Acute and chronic hepatitis in childhood leukemia: a multicentric study from the Italian Pediatric Cooperative Group for Therapy of Acute Leukemia (AIL-AIEOP).

The incidence of acute and chronic liver damage and its relation to hepatitis B virus (HBV) infection was evaluated in 164 consecutive children with acute leukemia seen in ten Italian hemato-pediatric units. Thirteen out of 164 children (7.9%) had acute hepatitis (AH) during treatment, while 8/90 (8.8%) showed an acute exacerbation of liver damage within 6 months after therapy withdrawal. Seven of the 13 children with AH while on therapy were HBsAg positive. In 12/13 cases, liver disease progressed to chronicity. Five of eight children who developed AH after completion of treatment were HBsAg positive. Eighty-nine patients (54.2%) developed biochemical evidence of chronic hepatitis during therapy; 48/89 were followed after cessation of treatment and 33 of them showed persisting evidence of liver cell necrosis. Thirty-three out of 133 children (24.8%) tested for serum HBsAg were found positive: 26 (78.7%) of them developed chronic hepatitis. Sixty-four out of 133 patients were evaluated after cessation of treatment: Chronic hepatitis persisted in 16/22 HBsAg-positive (72.7%) and in 17/42 HBsAg-negative (40.4%) children during follow-up. The outcome of these liver diseases after treatment withdrawal did not differ significantly in relation to HBV serology, suggesting that viral rather than toxic agents were responsible for liver damage also in most HBsAg-negative patients. The high incidence of chronic HBV infection in children with leukemia found in this multicentric study could suggest a need for active immunization with HBV vaccine, but the efficacy of such approach in this clinical setting is still to be validated.