Current issues in the management of paediatric viral hepatitis

Authors

  • Latifa T. F. Yeung,

    1. Rouge Valley Health System, Centenary Health Centre, Scarborough, ON, Canada
    2. Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada
    3. Department of Paediatrics, University of Toronto, Toronto, ON, Canada
    4. Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
    Search for more papers by this author
  • Eve A. Roberts

    1. Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada
    2. Department of Paediatrics, University of Toronto, Toronto, ON, Canada
    3. Department of Medicine, University of Toronto, Toronto, ON, Canada
    4. Department of Pharmacology, University of Toronto, Toronto, ON, Canada
    Search for more papers by this author

Correspondence
Latifa T. F. Yeung, MD, MSc, FRCPC, Rouge Valley Health System, Centenary Health Centre, Galaxy 12 Child & Teen Clinic, 2867 Ellesmere Road, 12th fl, Scarborough, ON M1E 4B9, Canada
Tel: +416 281 7476
Fax: +416 281 7313
e-mail: fung.yeung@utoronto.ca

Abstract

Viral hepatitis poses important problems for children. In preschoolers, hepatitis A virus (HAV) infection frequently causes acute liver failure. Vaccinating toddlers against HAV in countries with high endemicity is expected to decrease mortality. HAV vaccine demonstrates efficacy (comparable to immunoglobulin) as post-exposure prophylaxis. A recently developed vaccine against hepatitis E virus (HEV) may benefit fetal health, because pregnant women are most prone to acute liver failure as a result of HEV. Hepatitis B vaccine continues to demonstrate value and versatility for preventing serious liver disease. With chronic infection, undetectable levels of serum HBV DNA complement e-seroconversion as the preferred outcome measure; suppressed viral load correlates with long-term complications better than HBeAg status. Among Taiwanese children, low pretreatment HBV DNA (<2 × 108 copies/ml) strongly predicted response to interferon-α. Future paediatric studies must incorporate HBV DNA levels. The rationale for routine treatment of immunotolerant hepatitis B during childhood remains uncertain. Any treatment of chronic hepatitis B in childhood requires consideration of the risks and benefits. Childhood hepatitis C virus (HCV) infection results mainly from mother-to-infant transmission. Babies of HCV-infected women should be tested for serum HCV RNA at 1 month of age. If negative, confirmatory anti-HCV antibody testing may be performed between 12 and 15 months of age. Children with chronic hepatitis C may develop progressive fibrosis/cirrhosis, particularly in the setting of obesity and insulin resistance. Treatment of children chronically infected with genotype 2 or 3 is highly successful: combination therapy of pegylated interferon-α and ribavirin is well tolerated and superior to pegylated interferon-α alone.

Abbreviations
ALT,

alanine aminotransferase;

anti-HBe,

antibody to hepatitis B virus e-antigen;

HAV,

hepatitis A virus;

HBV,

hepatitis B virus;

HCC,

hepatocellular carcinoma;

HCV,

hepatitis C virus;

HEV,

hepatitis E virus;

SVR,

sustained viral response.

Viral hepatitis continues to be an important cause of liver disease in children, perhaps the most important cause in terms of numbers of children affected worldwide. Among hepatotropic viruses, the uncoated RNA viruses, hepatitis A virus (HAV) and hepatitis E virus (HEV) cause mainly acute hepatitis, including acute liver failure. The coated viruses, hepatitis B virus (HBV, a DNA virus) and hepatitis C virus (HCV, an RNA virus), may cause acute hepatitis or chronic hepatitis potentially progressing to cirrhosis and/or hepatocellular carcinoma (HCC). HBV and HCV may be transmitted from mother to infant by either in utero or perinatal infection. Advances in the clinical management of viral hepatitis – primary prevention by vaccination and treatment – have diminished some of the serious outcomes of these liver diseases. Nevertheless these diseases pose new challenges for the future. Viruses resistant to antiviral drugs or escape mutants beyond the reach of available vaccines represent iatrogenic alterations in the biology of these viruses. Some issues are socio-economic: poor living conditions, alternate lifestyles that predispose to spread of hepatotropic viruses and inaccessibility of antiviral treatment or preventive immunization. Whether the increasing prevalence of insulin resistance and obesity will affect the natural history of chronic viral hepatitis in childhood remains unresolved (Fig. 1).

Figure 1.

 Current management of paediatric hepatitis: strategies and challenges. HAV, hepatitis A virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HEV, hepatitis E virus; PEG-IFN-α, pegylated interferon-α.

Hepatitis A and acute liver failure

Among different parts of the world there is a notable difference in the predominant manifestation of hepatitis A. Generally, the clinical presentation of childhood hepatitis A is more severe with poverty and poor sanitation (1, 2). In North America and Europe, childhood hepatitis A is often subclinical. These children may transmit HAV to adults who then become symptomatic. A minority of children with hepatitis A develop non-specific gastro-intestinal symptoms or jaundice and occasionally require hospitalization for supportive care (3).

In less developed regions, HAV is the main aetiological agent for paediatric acute liver failure. Many affected children are in the preschool age bracket. Outcomes are unfavourable, with or without liver transplantation. In Latin America, the mortality rate from HAV-related acute liver failure among children and adolescents is 41% (2). Among 210 cases of paediatric acute liver failure from Argentina, 61% resulted from hepatitis A. Less than one-third of these patients survived without liver transplantation (4). These data, combined with cost-effectiveness analyses, strongly support the Argentine government's recent implementation of routine childhood vaccination against HAV (5, 6). In Turkey, HAV was the most common identifiable cause of paediatric fulminant hepatic failure, accounting for nine of 34 cases (26%) (7). In India, where the prevalence of HAV infection varies by geography and socio-economic class, approximately half of preschool-aged children are at risk for acute hepatitis A (8). HAV infection was identified in 40–53% of cases of paediatric acute liver failure among cohorts from New Delhi, West Bengal and southern India (9–11).

Hepatitis A vaccine

Since its introduction in 1995, the hepatitis A vaccine has proven to be an increasingly useful intervention for improving public health. In the USA, it has been safely administered to children over 12 months of age, concomitant with other routine immunizations, and consequent herd immunity has been established. Between 1995 and 2006, the incidence of hepatitis A in the USA declined to an all-time low with the greatest decline noted in states where routine vaccination of children was implemented since 1999 (12). These findings led to the 2006 recommendation for all children over 12 months of age to receive the hepatitis A vaccine, endorsed by the American Academy of Pediatrics (13, 14). Concerns that vaccination will shift the burden of disease to an older symptomatic group have raised the possibility that a booster dose may be necessary later in life in order to provide long-term protection (15). Thus far, the experience from using the combined hepatitis A and B vaccine has demonstrated durability of response for 7.5–10 years (16, 17). Table 1 summarizes the available formulations of hepatitis A vaccine, including the combined hepatitis A and B vaccine as well as combined hepatitis A and typhoid vaccine (the latter only recommended for individuals aged 16 years and older).

Table 1.   Formulations of childhood hepatitis A vaccines*
Vaccine brand nameImmunogen(s)For patients agedDose (given intramuscularly)Dosing schedule (months)
016–12 months
  • *

    Product Monographs from 2009 CPS (Compendium of Pharmaceuticals and Specialties) published by the Canadian Pharmacists Association.

  • †Unless otherwise specified.

  • HAV, hepatitis A virus; HBV, hepatitis B virus; ELISA, enzyme-linked immunosorbent assay.

Avaxim®– PaediatricInactivated hepatitis A vaccine12 months–15 years0.5 ml=80 antigen units HAVX X
Havrix® 720 JuniorInactivated hepatitis A vaccine12 months–18 years0.5 ml=720 ELISA antigen units HAVX X
Twinrix® Junior (standard 3-dose schedule)Combined hepatitis A and hepatitis B vaccine12 months–18 years0.5 ml=360 ELISA antigen units HAV and 10 μg HBVXXX (6 months)
Twinrix® (allows alternate 2-dose schedule)Combined hepatitis A and hepatitis B vaccine12 months–15 years1 ml=720 ELISA antigen units HAV and 20 μg HBVX X
Vaqta®Inactivated hepatitis A vaccine12 months–17 years0.5 ml=∼25 antigen units HAVX X (6–18 months)
ViVaximCombined purified Vi polysaccharide typhoid and inactivated hepatitis A vaccine≥16 years1 ml=25 μg purified Vi polysaccharide typhoid and 160 antigen units HAVX Give only HAV booster

The hepatitis A vaccine is also effective in the setting of post-exposure prophylaxis. Among healthy individuals aged 2–40 years in Kazakhstan (where HAV is of intermediate endemicity), index patients with hepatitis A were identified and then within 14 days of an index patient's initial symptoms, his/her exposed contacts received either vaccine or immunoglobulin. The vaccine (Vaqta®; Merck, Whitehouse Station, NJ, USA) demonstrated efficacy at least equal to, and probably better than, the traditional use of immunoglobulin as post-exposure prophylaxis. The authors pointed out that in some cases, the vaccine may be preferred over immunoglobulin given vaccine's higher availability, lower cost and longer-term protection (18). This randomized trial excluded individuals who were <2 years old, >40 years old, immunocompromised, or had chronic liver disease, and so in these individuals, immunoglobulin (at the standard post-exposure dose of 0.02 ml/kg of body weight) remains the first choice for post-exposure prophylaxis (19).

Given the emerging data for vaccine efficacy, it is timely and imperative that national groups reconsider their recommendations for universal hepatitis A vaccination. If implemented in Canada at age 1, the reported incidence and mortality from HAV is estimated to decrease by 60 and 56%, respectively, over the next 80 years (20). Internationally, vaccination programmes must consider variations in prevalence rates of HAV infection. For example, in India there is an ongoing epidemiologic shift of HAV prevalence from younger to older patients. Rates of anti-HAV vary geographically across India, and depend on socio-economic status, as well as degree of sanitation and personal hygiene. In such developing countries, the choice between mass vaccination vs. targeted vaccination (with screening for antibodies) remains a public health challenge, given the heterogeneous mix of susceptible and exposed individuals. To be economically feasible, the costs of the vaccine and screening must be evaluated in light of local prevalence rates. Certainly improved characterization of HAV prevalence and disease burden across different geographical regions, coupled with ongoing efforts to improve environmental hygiene will facilitate ultimate benefit from the HAV vaccine in such regions (8). Additionally, the human cost of the disease has to be given considerable weight when, as with acute hepatitis A, the outcome for a young child may be death or liver transplantation.

Hepatitis B vaccine

Universal hepatitis B vaccination has been justified in part as prevention of acute liver failure in children. The broader perspective envisions eradicating HBV worldwide. The success of the hepatitis B vaccine as the most effective method for combating hepatitis B continues. In Taiwan, 20 years after the implementation of the HBV vaccine, the rates of childhood chronic HBV infection and HCC have decreased dramatically (21). The cost of the monovalent hepatitis B vaccine has decreased substantially and worldwide accessibility to HBV vaccine continues to improve (15). Premature babies have been vaccinated safely with satisfactory immunogenic response (22). In Germany, administration of the (Sanofi Pasteur MSD, Allemagne, Germany) – which incorporates the hepatitis B vaccine into the traditional pentavalent diptheria, polio, tetanus, pertussis and Haemophilus influenzae type b vaccine – at 2, 4, 6 and 12 months of age has been well tolerated and effective at eliciting an immune response to all antigenic components (23). The long-term response from infant hepatitis B vaccination followed by a single booster dose remains durable among university-aged Taiwanese and 15-year-old Alaskans (24, 25). Preteens can receive hepatitis B vaccine along with menjugate vaccine in the same arm without loss of effectiveness of either vaccine (26). Finally, a recent case–control study from France further refutes any association between the hepatitis B vaccine and multiple sclerosis (27).

Escape mutants to the HBV vaccine have proven extremely rare, given the number of vaccinated individuals worldwide (28, 29). However, a recent pilot study of 46 HBV-vaccinated, HBsAg-negative Taiwanese children found that 10.9% harboured occult HBV infection – these children had low levels of HBV DNA and sequence analysis confirmed the presence of vaccine escape mutants (30). Reports of vaccine escape mutants demand surveillance: current vaccines cannot prevent infection by HBV variants with mutations in the S gene. Furthermore, these vaccine escape mutants may result from antiviral therapy (as drug-resistant mutants). Among 71 Spanish adults treated with at least 12 months of antiviral therapy, three patients revealed lamivudine-induced mutations that simultaneously altered the S gene, resulting a critical change in the C-terminal region of HBsAg. This resulted in decreased HBsAg–antibody binding. The authors reported that the lamivudine-resistant mutant was most likely to occur in HBV–HIV co-infected patients with genotype A. Changes in the HBV reverse transcriptase (drug-resistant mutation) overlapped with the portion of the HBV genome responsible for coding the envelope S gene, thus creating a vaccine-escape mutant. If these drug-induced HBV vaccine escape mutants prove transmissible, they could pose a serious public health concern. Altogether, the accumulating data emphasize the need to utilize antiviral drugs judiciously and favour strategies to minimize viral resistance (31).

Knowledge gaps in the of management of children with chronic hepatitis B

The management of children with chronic hepatitis B demands recognition of several key gaps in our understanding of this disease process (Fig. 2). First, the imperfect correlation between various short- and long-term outcomes of the disease must be recognized. Recent data emphasize the notion of decreased serum HBV DNA and normal aminotransferases as more predictive of favourable long-term outcomes compared with the traditional measures of e-seroconversion and loss of HBsAg. Secondly, even after incorporating viral load response with e-seroconversion rates, these short-term outcome measures of treatment outcome must always be compared against the natural history of the disease (i.e. placebo control or no treatment). Thirdly, the risks of treatment must be weighed against the benefit demonstrated beyond the baseline natural history. Finally, features of the virus itself need consideration; for example, the improved response to conventional interferon-α among different adult groups for genotype A compared with genotype D and in genotype B compared with genotype C (32). Such heterogeneity of both HBV and the host (route of transmission, ethnicity, co-infection with other viruses and comorbidity such as fatty liver disease) necessitates consideration for treatment on a case-by-case basis, following detailed discussion with the patient and family.

Figure 2.

 Knowledge gaps in the management of paediatric chronic hepatitis B. ALT, alanine aminotransferase; HBV, hepatitis B virus.

Short- and long-term outcomes of hepatitis B virus infection

Favourable short-term outcomes of HBV infection include loss of HBeAg with acquisition of anti-HBe (e-seroconversion), loss of HBsAg with acquisition of anti-HBs (s-seroconversion), suppression of serum HBV DNA (viral load) and possibly, histological improvement. Long-term outcomes that are most clinically relevant include decreased rates of cirrhosis, liver failure, and HCC related to HBV. Unfortunately, the measurement of long-term outcomes requires decades of follow-up, not yet available for most paediatric patients. Thus short-term outcomes of e-seroconversion and loss of HBsAg in treatment studies have traditionally served as imperfect surrogate markers for a favourable long-term prognosis.

Accumulating evidence expands upon the conventional assumption that e-seroconversion confers a long-term ‘healthy, inactive carrier state’ in all patients. Exceptions to this dogma include patients with genotype D (e.g. in the Mediterranean basin) who tend to have e-negative chronic hepatitis B, infection with a precore mutant virus (HBeAg negative but HBV DNA positive), and HBV-related HCC in childhood (most described cases are HBeAg negative) (33–35). Among 1336 consecutive Italian adults (mean age 49 years) with chronic hepatitis B who were referred to hospital, 86% were HBeAg negative. Furthermore, HBeAg status did not predict progression to cirrhosis (36). After a median 25-year follow-up, 70 Italian patients with chronic hepatitis B had a risk of liver-related mortality that correlated with sustained disease activity and ongoing HBV replication, independent of HBeAg status (37). Similarly, in Taiwanese patients, the chronic persistence of HBV replication, even at an arbitrarily defined low level of HBV DNA<104 copies/ml (2000 IU/ml) (38), appears to be the most important risk factor for complications of cirrhosis and HCC (39, 40). While many patients with e-seroconversion and normal aminotransferases (inactive carriers) indeed have lower rates of liver-related morbidity and mortality, the patients who are exceptions to this rule are distinguished by their high levels of HBV DNA and elevated aminotransferases (37).

Consequently, taking suppressed viral load, beyond e-seroconversion, as a favourable short-term outcome is expected to improve correlation with successful long-term outcomes. Given the fluctuating nature of HBV DNA levels over time, coupled with variable measurement techniques, a single measure of HBV DNA is difficult to interpret. A persistently low HBV DNA level (preferably below the limit of detection) is most reassuring. This revision to practice may prove particularly relevant to individuals infected in early childhood (before 2 years of age, mainly Asians and Africans), compared with those infected later in life (mainly Caucasians) (41, 42). These conclusions regarding the improved prognostic value of chronic persistently high serum HBV DNA are based on the extrapolation of adult data and therefore deserve confirmation by longitudinal cohorts of patients followed from early childhood.

Treatment options and their impact on the natural history of childhood hepatitis B virus infection

Among children with chronic hepatitis B, treatment options studied using randomized placebo-controlled trials thus far include interferon-α, lamivudine and adefovir (see Table 2). In general, higher baseline alanine aminotransferase (ALT) and lower baseline HBV DNA tend to be associated with treatment response. While some studies have described a initial course of steroid (prednisone priming) before treatment with interferon-α, only three studies allow for meaningful interpretation by randomizing children into three groups: prednisone with interferon-α, interferon-α alone and no treatment (47–49).

Table 2.   Treatment options for paediatric chronic hepatitis B
 Outcomes*Reference
Loss of HBeAgUndetectable HBV
DNA
Loss of HBsAgViral resistance
  • *

    For interferon, outcomes measured at 6–48 months after cessation of therapy; for lamivudine, outcomes measured at end of 52 weeks therapy, although durable response was >75% in (treated and control) patients who lost HBeAg in this study up to 4 years later (46).

  • For adefovir, outcomes were measured at end of 48 weeks therapy. The primary endpoint was reported as HBV DNA<1000 copies/ml and normal ALT at end of 48 weeks of treatment, although this significant finding was largely confined to adolescents (aged 12–18 years), with no significant benefit of adefovir detected among children <12 years of age, compared with placebo.

Interferon-α31.1%33.9%5.5% Meta-analysis of 10 randomized controlled trials
542 children
Lin et al. (43)
Controls12.4%16.2%1.2%
P-valueP<0.0001P<0.0001P=0.02
Lamivudine
2 mg/kg (max 100 mg) p.o. OD × 52 weeks
23%No data19% YMDD mutationsRandomized placebo-controlled trial
n=191 lamivudine
n=97 placebo
Jonas et al. (44)
Placebo13%No data
P-valueP=0.04
Adefovir
0.25–0.3 mg/kg (max 10 mg) p.o. OD × 48 weeks
15.9%19.1%0.9%NoneRandomized placebo-controlled trial
n=115 adefovir
n=58 placebo
Jonas et al. (45)
Placebo5.3%1.7%No data
P-valueP=0.051P<0.001

Adults chronically infected with HBV enjoy a wider range of treatment options than children. Licensed medications include lamivudine, interferon-α, adefovir dipivoxil, peginterferon α-2a, entecavir, telbivudine and tenofovir disoproxil fumarate. Treatment studies of pegylated interferon-α appear promising, and newer generations of oral nucleosides and nucleotides (e.g. entecavir, tenofovir and clevudine) appear to offer increasingly potent viral suppression with lower rates of viral resistance (50–52). A recent randomized comparison of tenofovir against adefovir among adults with HBeAg-positive as well as HBeAg-negative chronic hepatitis B demonstrated a superior antiviral efficacy of tenofovir with similar safety profile compared with adefovir. Particularly promising was the lack of viral resistance mutations up to week 48 (53). Furthermore, inspired by the success of combination treatment for human immunodeficiency virus and HCV infection, adult studies are beginning to examine the merit of combination therapy for chronic hepatitis B. Although combination therapy of a nucleotide and nucleoside analogue does not improve treatment efficacy (compared with monotherapy), there may be a lower rate of viral resistance (38, 54). This consideration is important because treatment-provoked mutations in HBV appear to worsen the long-term prognosis in adults.

Among predominantly non-Asians, successful treatment of paediatric hepatitis B by interferon-α appears to result in earlier e-seroconversion, when compared with the natural history of HBV infection. Without treatment, many children will still naturally seroconvert. Among 107 Italian children with chronic hepatitis B, treatment with interferon-α was associated with clearance of HBeAg in 60% at 5 years of follow-up – similar to the HBeAg-clearance rate of 65% among 59 controls (55). The authors suggested that children with prominent disease activity who responded early to treatment might exhibit a higher rate of s-seroconversion, as seen in four patients. In a multi-ethnic Montreal cohort, 40.2% of 174 HBV-infected children e-seroconverted (with or without treatment) after a mean follow-up of 4.5 years. Asian children in this cohort who tended to acquire HBV via maternal-infant transmission had a lower rate of e-seroconversion compared to children born in Canada who tended to acquire HBV via horizontal transmission (75 vs. 94%, respectively, at 13 years) (56).

Disappointingly, among Asian children, interferon-α does not improve the natural history when HBV DNA suppression is incorporated into the outcome. In a recent carefully matched case-controlled study from Taiwan describing interferon-α treatment (3 MU/m2/day three times a week for 24 weeks) of 21 children aged 1.8–21.8 years (median age 14 years), there was no difference in the rate of virological response (defined as e-seroconversion and decrease of HBV DNA<102 copies/ml) compared with control patients: 41 vs. 44% at 1 year and 88 vs. 89% at 6 years. Follow-up ranged from 6.5–12.5 years (57). Figure 3 illustrates the increasing rate of HBeAg loss over time, regardless of exposure to interferon-α among different cohorts of non-Asian and Asian children with chronic hepatitis B. Taken together, these data challenge the consensus that interferon-α confers long-term benefit for children with chronic hepatitis B. Whether long-term outcomes of cirrhosis and HCC are improved for children treated with interferon-α remains unknown. However, many adults treated with interferon-α continue to have detectable HBV DNA levels >2000 IU/ml (the strongest independent predictor for cirrhosis and HCC) and most studies fail to demonstrate a significant decrease in long-term rate of HCC (58–60).

Figure 3.

 The rate of HBeAg loss increases over time, regardless of exposure to interferon among different cohorts of children with chronic hepatitis B. For Taiwan and Italy cohorts: Black column represents children treated with interferon. White column represents controls (untreated children, carefully matched in Taiwan cohort). For Canada cohort: Black column represents Asian-born children. White column represents non-Asian-born children. Twenty-seven (16%) of the total 174 Canadians were treated with interferon. Interferon accelerated e-seroconversion by 3 years, but did not influence the proportion that seroconverted over time.

Three meta-analyses of controlled trials comparing conventional interferon-α to controls among children with chronic hepatitis B all report the overall superiority of interferon-α in generating e-seroconversion, clearing HBV DNA, normalizing ALT, clearing HBsAg, but not s-seroconversion (i.e. appearance of anti-HBs) when compared with the natural course of chronic HBV infection (43, 61, 62). One meta-analysis of 10 controlled studies involving 542 HBV-infected children reported an overall rate of e-seroconversion from interferon-α of 30.4% compared with control rate of 12.8% [odds ratio 2.9, 95% confidence interval (CI)=1.56–5.39, P=0.0008] (43). It is helpful to bear in mind that meta-analyses are subject to the same sources of heterogeneity as their original studies: different viral genotypes, different hosts, different modes of transmission and different durations of follow-up. Nonetheless, these studies highlight the overall trend that acceleration of e-seroconversion by interferon-α in the short term likely holds less impact over time as patients naturally seroconvert. What is unclear is whether earlier e-seroconversion entails less liver damage.

Some suggest that treatment with interferon-α in younger children (<5 years old) is more effective compared with older children (63, 64). However, when restricting comparison only to patients who received interferon-α, the recent Taiwanese case–control study demonstrated that lower (<2 × 108 copies/ml) pretreatment levels of HBV DNA (P=0.008) proved to be an even stronger indicator of treatment response than younger age (P=0.03) (57). Neither initial nor peak ALT correlated with treatment response. These recent data emphasize the growing recognition of HBV DNA levels as an important predictor of outcome.

Among 23 immunotolerant HBV-infected children (17 of whom were Asian) with normal ALT, treatment using lamivudine and interferon-α resulted in an e-seroconversion rate of 22% (95% CI 5–39%) (65). However, data from 40 untreated immunotolerant HBV-infected adults report e-seroconversion in 67% (95% CI 52–82%) at a median age of 30.7 years (66). Therefore, each patient must choose between an e-seroconversion success rate of under 40% during childhood (at the cost of interferon-α therapy) compared with the up to 80% likelihood of natural e-seroconversion at approximately 30 years of life. These limited, uncontrolled data raise the question: Should all immunotolerant HBV-infected children undergo routine treatment to accelerate e-seroconversion in 22%? Such potential benefits must be weighed against the adverse effects of interferon-α. Most clinicians and families will likely hesitate to treat such asymptomatic children, recognizing that severe disease outcomes such as cirrhosis, liver failure and HCC are extremely rare (<3%) in childhood (Table 3) (34, 35, 56, 67, 68). To properly address the safety and efficacy of treating immunotolerant children, a large, multi-centre, randomized, controlled trial with long-term outcomes such as of cirrhosis, liver failure and HCC, would be indispensable. The non-treatment arm of this study would also serve to elucidate the long-term natural history of childhood hepatitis B as it evolves through adulthood. The strategic use of administrative databases in a universal health-care setting would greatly facilitate such measurement of long-term outcomes, if coordinated early into the study design.

Table 3.   Paucity of long-term outcomes described in paediatric chronic hepatitis B
AuthorYearPlace# liver biopsies# cases of cirrhosis# cases of HCCDuration of follow-up
  • *

    No pathology available on this cohort of 173 children; single case of cirrhosis based on diagnostic imaging only.

  • HCC, hepatocellular carcinoma.

Iorio2007Italy571 (1.8%)05–23 years
Zacharakis2007Greece01*01–12 years
Bortolotti2006Italy914 (4.4%)2 (2.2%)Up to 29 years
Marx2002Canada411 (2.4%)04 weeks–16 years
Fujisawa2000Japan5202 (3.8%)3–22 years
Total2417 (2.9%)4 (1.7%) 

Although several paediatric studies have reported the use of steroid priming before interferon-α, and no significant adverse events have been related to such steroid use, the additional value of steroid pretreatment remains unimpressive (47–49, 69–75). In particular, among the three paediatric studies that randomized children into groups of prednisone with interferon-α, interferon-α alone and no treatment, no statistically significant short-term benefits (e.g. short-term rate of HBeAg loss) of steroid priming compared with interferon-α alone were demonstrated (47–49). These studies were heterogeneous in many regards: varying patient population (children of varying age, duration of infection, mode of transmission, ethnicity and likely genotype), varying sophistication of outcome measures (studies published between 1991 and 2006), and varying duration of follow-up. However, in this study with the longest follow-up detailed at 7 years, Boxall and colleagues suggest that steroid priming may be of benefit in the long-term, citing a higher longer-term rate of e-seroconversion, which might not have been measurable in previous studies of shorter follow-up duration (Fig. 4). Adult data may support this finding: a systematic review of interferon-α alone or in combination with steroids found that steroid priming among adults improved the rate of HBeAg loss and HBV DNA. Disappointingly, this meta-analysis also found that steroids failed to improve other pertinent outcome measures such as rates of e-seroconversion, loss of HBsAg and normalization of aminotransferases (76).

Figure 4.

 Rate of HBeAg loss in randomized studies of interferon with and without pretreatment steroids compared with controls. White bars represent untreated controls, grey bars represent children treated with interferon alone, and black bars represent children randomized to interferon with pretreatment steroids. *Only after prolonged follow-up (rates estimated by Kaplan–Meier method at 5 years) does pretreatment steroid appear to improve the rate of HBeAg loss compared with treatment with interferon alone.

Risks and benefits of treatment of chronic hepatitis B

The potential benefits of treatment include earlier e-seroconversion by approximately 3 years (55, 56), a shorter window of exposure to high titres of HBV DNA yielding a lower likelihood of long-term disease, possible psychological relief, and a decreased risk of transmitting the virus to others. These benefits must be weighed against the risks of treatment including the side effects of interferon-α: flu-like symptoms with fever, leucopaenia, thrombocytopaenia, alopecia, myalgia, malaise, anorexia, diarrhoea and nausea and vomiting. These side effects are generally mild, self-limited and tolerated by most children (57). Children under 12 months of age cannot be treated with interferon-α, given the risk of spastic diplegia (77, 78). Other problems of treatment include the inconvenience of interferon-α injections and financial cost. By contrast, oral antivirals (such as lamivudine and adefovir) avoid the need for injection of medicine and involve minimal side effects, but carry a highly worrisome risk associated with viral resistance profiles. Developing resistance may severely limit future treatment options. Resistance to lamivudine is highest, with rates up to 70% after 5 years, whereas newer nucleotide/nucleoside analogues have lower resistance rates. In some cases, nucleotide/nucleoside analogue medication may become a commitment of infinite duration for the child if drug discontinuation results in significant re-emergence of HBV. Whether or not more rapid e-seroconversion ultimately results in overall improvement in disease outcome in terms of cirrhosis, liver failure and HCC also remains unclear, particularly for children (79).

The decision to treat a child with chronic HBV infection requires thoughtful consideration. Arguments against routine treatment of chronic immunotolerant HBV infection recognize that the disease generally runs a benign course and some children will naturally undergo e-seroconversion over time (67). As such, for most children watchful waiting with periodic surveillance of viral markers will outweigh the risks of the side effects of interferon-α. With time, newer antivirals (such as entecavir with lower resistance rates) may become available for treating childhood chronic hepatitis B. Lower resistance rates will provide the necessary confidence to expose healthy HBV-infected children to antiviral therapy. On the other hand, in those paediatric cases of chronic hepatitis B with persistently elevated aminotransferases, histological evidence of significant inflammation or fibrosis, detectable HBeAg and significant levels of serum HBV DNA (>104 copies/ml), treatment to halt the hepatic damage is warranted.

The role of liver biopsy

The results of a liver biopsy may help determine management. For a minority of patients, the finding of significant fibrosis or high-grade inflammation may favour prompt treatment. However, most will demonstrate near-normal histology, and such data may provide sufficient reassurance to defer treatment until the child is older while also allowing more time for spontaneous e-seroconversion to occur. Advocates for obtaining a liver biopsy before treatment recognize the value of establishing a baseline measure of histological disease. A liver biopsy may also confirm that aminotransferases are elevated as a result of HBV infection or address the role of concomitant disease processes.

Heterogeneity of hepatitis B virus and host

Some have found an improved response to conventional interferon-α among different adult groups for genotype A compared with genotype D and in genotype B compared with genotype C (32). In Taiwanese children, however, superiority of response to treatment by genotype B compared with genotype C was not observed. In this recent case-controlled study, development of a precore mutant prior to initiation of interferon-α treatment likewise did not predict treatment response (57).

Factors affecting the host include route of transmission, ethnicity, co-infection with other viruses and comorbidity such as fatty liver disease. Route of transmission and ethnicity may be related to surrogate markers for the same characteristic. Asians tend to acquire infection perinatally or in early childhood and generally e-seroconvert later, compared with non-Asians who tend to acquire HBV infection later in life (56). One meta-analysis attempting to clarify these host characteristics concluded that vertical transmission of HBV, regardless of race, was predictive of a poor response to interferon-α (62).

Approach to management of hepatitis B in childhood given knowledge gaps

Consequently, the management of children with chronic hepatitis B deserves revised considerations. Vaccination in early infancy should be universal; in the future many cases of chronic hepatitis B will be in those children who did not respond to hepatitis B vaccine for some reason. For both treated and untreated patients, the traditional outcome of e-seroconversion must be evaluated by HBV DNA monitoring to identify those who continue to have persistent HBV replication. Asymptomatic children, particularly with normal serum aminotransferases, may be given time to naturally e-seroconvert with loss of HBV DNA. Provided that the clinical course remains benign, treatment may be strategically deferred to adulthood, as better drug options (with notably a lower risk of developing viral resistance) continue to emerge. Periodic monitoring should help identify the minority of children whose clinical course is not benign (e.g. significantly elevated aminotransferases and fibrosis on liver biopsy). Such patients deserve consideration for treatment on an individualized basis, preferably in the setting of a clinical trial. These patients hold higher priority for treatment trials compared to immunotolerant children. Any study to evaluate drug efficacy properly must incorporate a placebo control; the safety and efficacy of monotherapy must be demonstrated before combination therapy can proceed. Above all else, outcome measures must incorporate viral load as well as longer-term outcomes of cirrhosis, liver failure and HCC. As there are no reliable predictors to identify the rare child who develops cirrhosis or HCC, long-term periodic monitoring of all patients infected with HBV remains the most conservative approach. Screening for HCC relies on liver ultrasound and serum α-fetoprotein every 6–12 months (38).

Key issues relating to hepatitis C in childhood

With improvements in detection of HCV, transfusion-associated hepatitis C has become extremely rare in countries where adequate facilities for screening blood are available. Most chronic hepatitis C in children is because of mother-to-infant transmission. The rate of such infection is strikingly lower than with HBV, but it may be sufficient to generate approximately 50 000 new cases worldwide each year (80). By comparison to chronic hepatitis B, chronic hepatitis C appears potentially curable in many patients. The slower progression of liver disease poses problems for timing treatment.

Testing infants for vertically transmitted hepatitis C

North American guidelines previously declared that babies born to women infected with HCV should be tested using antibody to HCV at 12–18 months of age (81, 82). The rationale for this recommendation is purely cost effective: earlier testing may be less reliable and thus will often require subsequent confirmatory testing, and earlier tests using HCV RNA are more expensive than antibody testing. Such guidelines ignore the psychological burden imposed on new mothers who must worry about their baby's unknown HCV status for upwards of 1 year. Newer data dictate that these recommendations be revised in the near future.

The rate of maternal–infant transmission of HCV is approximately 5% (80, 83, 84). Despite this seemingly low percentage, all babies of women infected with HCV deserve testing. Only then can families receive proper monitoring and counselling. Affected infants can be vaccinated against both hepatitis A and B and be prioritized for future treatment. Perhaps the most compelling reason for testing these babies is the converse statistic: 95% of mothers will enjoy an overwhelmingly improved quality of life after confirming that their baby is not infected with HCV.

Among 1104 babies of chronically HCV-infected women, the clearance of passively transferred maternal antibody occurred in 95% of babies by 9–15 months of age (85). Thus before 9–15 months of age, one must rely on HCV RNA testing to identify HCV infection. Polymerase chain reaction (PCR) testing cannot be a simple gold-standard: HCV RNA levels may take time to reach the threshold for PCR detection in many neonates, levels of HCV RNA may fluctuate (yielding a pattern of intermittent viraemia by PCR testing) and accelerated spontaneous clearance may also occur.

The European Paediatric HCV Network prospectively studied 357 HCV-exposed infants and found that the sensitivity of PCR for HCV RNA was 22% at birth and increased dramatically to 70–85% after 1 month of age. For this study, antibody status at or beyond 18 months of age served as the gold-standard. Meanwhile, the specificity of the test remained high (98%) regardless of age. Compared with a single test, the sensitivity of two consecutive positive PCR tests and specificity of two consecutive negative PCR tests were marginally improved (86).

Therefore, a minimal testing algorithm of HCV RNA testing after 1 month of age (perhaps at the routine 2-month well baby visit) would be suggested by current literature. If the PCR test is negative for HCV RNA, then a confirmatory negative antibody should be documented after 12–15 months of age. If the initial HCV RNA proves positive, then that infant will require regular testing for HCV RNA and ALT every 6 months to determine whether chronic infection or spontaneous clearance ensues.

Natural history of chronic hepatitis C

An optimistic perspective recognizes that spontaneous clearance of HCV may occur in approximately one-third of children (87, 88) and most liver histopathology is mild in childhood. The pessimistic viewpoint acknowledges that the remaining majority with persistent infection deserve consideration for treatment because extensive liver injury and cirrhosis may occur. An Egyptian study of 43 children with chronic hepatitis C noted mild hepatic fibrosis in 47% and moderate to severe fibrosis in 26% (89). By contrast, of 121 American children with chronic hepatitis C, 3% had severe inflammation, five had bridging fibrosis and two (1.6%) had cirrhosis (90). Similarly, an Italian cohort of 322 children with chronic hepatitis C found six cases (1.8%) of cirrhosis (91).

Effect of obesity and insulin resistance on chronic hepatitis C

The degree to which the increasing prevalence of childhood obesity (92) exacerbates chronic hepatitis C in children remains unclear. The prospective American study (part of the pegylated interferon-α and ribavirin study protocol) focusing on liver pathology findings reported that steatosis was associated with ALT and body mass index (normalized by age and gender). These results suggest that over time progressive liver disease is possible, particularly if infected children develop comorbid risk factors such as obesity and insulin resistance (90, 93). On the other hand, obesity is not a prerequisite for severe hepatitis C in childhood. In the larger, retrospective/prospective Italian study spanning 15 years, among the six cases of biopsy-validated cirrhosis, only four showed steatosis and none of the children was obese (91). Mechanisms of steatosis in chronic hepatitis C appear to depend on genotype. Steatosis with infection by HCV genotype 3 tends to correlate with levels of intrahepatic viral replication and resolve upon sustained viral clearance. Steatosis development during infection by non-genotype 3 HCV depends upon host factors of insulin resistance. Additionally, such steatosis does not resolve with antiviral therapy. The genotype-specific association with steatosis does not extend to outcome of hepatic fibrosis. An Australian study of 346 adults with chronic hepatitis C recently demonstrated that insulin resistance is a major independent determinant of hepatic fibrosis, independent of genotype and degree of steatosis. This large, prospective trial enrolled only untreated, non-diabetic adults with chronic hepatitis C of either genotype 1 or 3 (94).

While paediatric data clearly show that some children with chronic hepatitis C also have non-alcoholic fatty liver disease, an outcome of worsened fibrosis remains to be proven. If adults with chronic HCV infection and insulin resistance tend to develop more fibrosis, likewise over time HCV-infected children with insulin resistance may develop more severe liver disease. The extent to which insulin resistance (clinically manifested by the increasing prevalence of paediatric obesity and diabetes) will exacerbate childhood chronic hepatitis C has become a significant concern.

Treatment of chronic hepatitis C

Treatment of children infected with genotype 2 or 3 is highly successful. The UK HCV National Register Database reported treatment outcome for 110 cases of paediatric HCV infection (31 treated with interferon-α monotherapy and 78 received combination therapy of interferon-α with ribavirin). The sustained viral response (SVR: undetectable serum HCV RNA 6 months following discontinuation of therapy) among genotype 1 was 18%, markedly lower than the SVR for non-genotype 1 of 79% (95). Combination therapy of pegylated interferon-α and ribavirin was reported for 30 Spanish children with chronic hepatitis C with SVR of 50% (response in all three patients with genotype 3 but only 12 of 27 patients with genotype 1 or 4). Treatment using pegylated interferon-α and ribavirin is well tolerated among children (96, 97). Results from a multicentre placebo-controlled US study found pegylated interferon with ribavirin superior to pegylated interferon alone in 114 children (SVR 53 and 21%, respectively, P<0.001). Among the 55 children randomized to receive pegylated interferon and ribavirin, SVR reached 47% for those infected with genotype 1 and 80% for those with non-genotype 1 (90, 98, 99). Among adults infected with genotype 1, studies using HCV NS3/4a protease inhibitor telapravir in combination with pegylated interferon appear to substantially suppress viral load (100). If further promising results are confirmed, then paediatric trials for children infected with genotype 1 should follow. The durability of SVR response in the treatment of hepatitis C is robust for the vast majority of patients. Among 344 adolescents and adults who achieved SVR following interferon-α treatment of some sort, HCV RNA remained undetectable in follow-up samples of serum and peripheral blood mononuclear cells and detectable in only two of 114 liver samples after a median follow-up of 3.3 years (range 0.5–18 years) (101). However, case reports have described detectable serum HCV RNA within weeks of achieving SVR when prednisone was used to treat bronchitis or immune suppression was administered for renal transplantation (102).

Prevention of hepatitis E

A vaccine for hepatitis E has recently been developed. A randomized phase 2, double-blind placebo-controlled trial of 2000 healthy Nepalese adults (mostly men) proved to be safe and immunogenic (103). A second study of the vaccine in southern China involving 457 adults and 155 high school students confirms that HEV vaccine prevents clinical disease from HEV (104). Whether the vaccine can also prevent asymptomatic infection remains unclear. The durability of the protection will also need to be established. Nevertheless, the continuing work to define the feasibility of the vaccine for high-risk groups should eventually benefit those at highest risk of acute hepatic failure from HEV: pregnant women living in endemic regions (southeast and central Asia, north and west regions of Africa, Middle East and Mexico). For these women, the case fatality rate of hepatitis E reaches 25% during the third trimester of pregnancy. Those who survive such illness suffer high rates of spontaneous abortion and stillbirths (105, 106). Given the lack of treatment options for hepatitis E, the HEV vaccine represents the leading candidate for protecting the unborn children at risk.

Conclusion

In the ongoing struggle to protect children from the major hepatotropic viruses, much progress has been made through strategies of either preventive vaccination or antiviral therapy. The availability of both hepatitis A and B vaccines has reduced the burden of disease from HAV and HBV infection for many children, particularly in the developed world. The new hepatitis E vaccine holds great promise, especially for unborn children of susceptible pregnant women. Over time, these benefits are expected to increase further as international health policy rises above the socio-economic barriers and finds ways to provide these vaccines to less developed regions in the world. Antiviral therapy for both hepatitis B and C offers hope to many chronically infected children. However, decisions to treat childhood chronic hepatitis B must recognize the limitations in data for successful long-term disease outcomes. Judicious use of antiviral therapy is imperative to minimize the development of drug-induced HBV escape mutants, some of which may become resistant to current vaccines. Hepatitis C is potentially curable, especially for those with genotypes 2 and 3, but such success may be threatened by the increasing prevalence of childhood obesity and insulin resistance. Ensuring a healthy childhood, unburdened by the problems associated with viral hepatitis, is an important and attainable goal worldwide.

Acknowledgements

The authors have no relevant conflicts of interest to acknowledge.

Ancillary