What evidence to support antiviral treatment in children
with chronic hepatitis B?
Journal: Antiviral Therapy
Manuscript ID: AVT-13-COM-3005
Manuscript Type: Commentary
Date Submitted by the Author: 29-Jul-2013
Complete List of Authors: Iorio, Raffaele; University Federico II, Department of Translational Medical
Tufano, Maria; University Federico II, Department of Translational Medical
Giagnorio, Maria; University of Molise, Medicine and Health Sciences
Spagnuolo, Maria; University Federico II, Department of Translational
Giannattasio, Antonietta; University of Molise, Medicine and Health
Keywords: Hepatitis, Natural history, Paediatrics
International Medical Press: Antiviral Therapy
What evidence to support antiviral treatment in children with chronic hepatitis B?
1Raffaele Iorio, MD, 1Maria Tufano, MD, 2Maria Giovanna Giagnorio, MD, 1Maria Immacolata
Spagnuolo, MD, 2Antonietta Giannattasio, MD, PhD
1Department of Translational Medical Sciences, University Federico II, Naples, Italy
2Medicine and Health Sciences Department, University of Molise, Campobasso, Italy
Antonietta Giannattasio, MD, PhD
Medicine and Health Sciences Department
University of Molise
c/da Tappino, 86100, Campobasso, Italy
Mail: email@example.com; firstname.lastname@example.org
Running head: Treatment of children with hepatitis B
Word count: 1505
Conflict of interest declaration: none of the authors have commercial or other associations that
pose a conflict of interest.
List of abbreviations: Chronic hepatitis B, CHB; hepatocellular carcinoma, HCC; interferon, IFN;
nucleoside analogues, NA; chronic hepatitis C, CHC.
Page 1 of 9 International Medical Press: Antiviral Therapy
Many questions are unanswered on the optimal management of chronically HBV-infected children.
Chronic hepatitis B is generally a mild disease in children; response to therapy is partial and limited
to specific subgroups; available drugs have no proven advantage on long-term course versus no
treatment, and are hampered by numerous limits. Studies on natural history of chronic hepatitis B
and the long-term results of the therapeutic schedules adopted so far should be critically appraised.
A balance between the potential benefits of the treatment and its side effects, and the spontaneous
course of the disease left untreated should be made.
Children; chronic hepatitis B; interferon; lamivudine; long-term outcome.
Page 2 of 9International Medical Press: Antiviral Therapy
Hepatitis B is an important disease worldwide and chronic infection is a cause of considerable
morbidity . Although several guidelines on chronic hepatitis B (CHB) are available, many
questions remain unanswered on the optimal managementof chronically HBV-infected children.
One of the most debated issues in literature is whether treatment can modify the long-term course of
CHB acquired in childhood. In fact, the studies on long-term outcome of children with CHB have
failed to demonstrate that treated children versus untreated patients have advantages in terms of
survival and risk of cirrhosis and hepatocellular carcinoma (HCC) [2,3]. Very recently, a review on
the management CHB in children and adolescents has been published . The Authors stated that
CHB acquired in childhood is a mild disease with a low rate of decompensated cirrhosis and HCC;
response to available therapies is partial; interferon (IFN) and/or nucleoside analogues (NA) do not
seem to provide any advantage on long-term course versus no treatment . Nevertheless, the
Authors proposed an algorithm to guide treatment decision, in which liver biopsy was
recommended in presence of abnormal transaminases and high levels of HBV DNA in order to treat
children with moderate/severe inflammation/fibrosis . Patients with mild inflammation/fibrosis
were considered for treatment in case of a family history of HCC .
On the basis of this review and the studies performed so far, a critical appraisal of the best available
evidence on this topic would be desirable.
It is well known that CHB disease is characterized by three phases: the first is the immune tolerance
phase, with near normal histology, high concentrationsof HBV DNA, and HBeAg positivity; the
second is the immune clearance phase, with seroconversion from HBeAg to antibody against
HBeAg accompanied by active inflammationand fibrosis and fluctuating serum alanine
transaminase (ALT) concentrations; the residual phase is characterized by low concentrationsof
HBV DNA and normal concentrations of ALT . Immune tolerance phase is typical of vertically-
infected children and is mainly observed in Eastern countries. It is widely accepted that the
phenomenon of seroconversion to anti-HBe more commonly occurs in patients with elevated ALT
Page 3 of 9International Medical Press: Antiviral Therapy
levels, while the rate of clearance of HBeAg is much lower in carriers who are in the immune
tolerant phase and in immunocompromised subjects.
Studies demonstrating a risk of disease progression exclusively limited to viremic patients with high
transaminases are lacking. In Eastern countries, where, before the implementation of mass
vaccination programs, HBV infection was generally acquired at birth with a consequent prolonged
immune tolerant phase, CHB was associated with a lifelong higher chance of developing cirrhosis
or HCC . Since not only the presence but also the duration of immune active phase is associated
with a poor prognosis, duration of this phase should be taken in account to consider liver biopsy and
treatment . Transaminases and HBV DNA levels alone probably are not sufficient to guide the
decision to do biopsy or not. Furthermore, we cannot ignore that currently there is a drastic
reduction in the use of liver biopsy [6,7]. As for the role of family history of HCC, more details
(degree of kinship, age at onset of HCC, presence of coinfections or other risk factors for HCC)
should be considered in order to select candidates to treatment.
The real indications to antiviral therapy in pediatric CHB should be revaluated. Although it is true
that the impact of currently available treatments on long-term course of disease is hampered by a
chronic delay in licensing new drugs as compared to adults, on the other hand, we cannot state that
the use of drugs, already approved for adults, may significantly improve the prognosis of children.
Unfortunately, these drugs are able to improve selected biomarkers of infection, but their real
impact on long-term course of disease and their safety profile are still unclear . This might
support the use of drugs in a number of patients larger than necessary. Far to define therapy of
pediatric CHB as a case of disease mongering, we think that a treatment should be performed in
children only when its efficacy is clearly documented. In this context, impact of the available
therapies on clinical endpoints and their costs in terms of medical expenses and side effects should
be weighed. The look for an “ideal therapy” can lead to consider a mild disease as a severe one with
an excess of medicalization.
Page 4 of 9 International Medical Press: Antiviral Therapy
As for the real impact of the currently available treatments for children with CHB, a more critical
evaluation of the short and mid-term results (i.e.: negativization of HBeAg, seroconversion to anti-
HBe, suppression of viral replication) versus the long-term results (i.e.: survival rates, percentages
of decompensated cirrhosis and HCC) must be done. The majority of available studies were
designed to assess short term effects of therapies on intermediate virological, histological or
biochemical outcomes, but no good evidence that antiviral drugs commonly used in CHB could
prevent cirrhosis, liver decompensation, cancer or mortality exist . Most of children with CHB
achieve HBeAg serocoversion even without treatment, and spontaneous HBeAg seroconversion
seems to have a favorable outcome [2,3,9]. In our pediatric series, no advantage at final evaluation
in terms of normalization of transaminases, clearance of HBV DNA and anti-HBe seroconversion
was observed between IFN-alfa treated and untreated children . This data was confirmed at an
additional 5-year follow-up (unpublished data). Furthermore, it is still unknown whether earlier
anti-HBe seroconversion can modify the natural history of the disease, considering thattwo-thirds of
cirrhosis-related complications and hepatocellular carcinomas in Asian patients with hepatitis B
occur after HBeAg seroconversion .
Finally, HBsAg seroconversion, a desirable treatment endpoint because it reduces but does not
eliminate the risk of HCC, occurs only in a minority of cases . In this, CHB differs substantially
from chronic hepatitis C (CHC). In CHC, a sustained clearance of serum HCV RNA is obtained in
50%-60% of patients treated with pegylated-IFN plus ribavirin and, once achieved, it is associated
with a long-term clearance of HCV, which is regarded as a virologic “cure,” with an improved
morbidity and mortality [11,12]. In contrast, in patients with CHB, a definitive clearance of serum
HBV DNA is more rarely observed in instances of favorable response to therapy. In a recently
published systematic review (16 RCTs identified, 4431 patients) on the effectiveness of antiviral
treatment for CHB in adults, the authors underlined that no treatment improved all outcomes
(virological, biochemical and histological outcomes, mortality, occurrence of cirrhosis or liver
cancer) . Evidence about the comparative effectiveness of combined therapies (as peg-IFN plus
Page 5 of 9International Medical Press: Antiviral Therapy
lamivudine) was limited and few drugs demonstrated sustained benefits superior to placebo .
Furthermore, in CHB, low serum HBV DNA did not eliminate the risk of progression. This point
deserves attention because only a complete viral eradication should be considered a good result of
therapy. Of course, we are aware that the decline in HBV viral replication is important to reduce the
risk of transmission, especially in areas where the vaccine is not extensively used. Further, we are
conscious that in the upcoming years the combined use of new antiviral treatments could
significantly improve the virological response rates, similarly to what achieved in patients with
AIDS. But, at the present time, the numerous limits of the therapy for CHB in children (high costs,
side effects, risk of developing antiviral resistance, poor advantages on long-term versus untreated)
cannot be ignored. In addition, NA, the second line therapy for children, is hampered by the risk of
emergence of resistant mutants . As a consequence, a child harboring a resistant HBV strain will
have a limited number of effective treatment options as an adult. It is also to note that transmission
of drug-resistant strains to uninfected person could occur and could have public health implications.
In conclusion, on the basis of the literature evidence, several aspects should be considered in the
management of children with CHB:
1. There have been few studies with a sufficiently long follow-up period to calculate the risk of
progression towards serious liver disease in children with CHB.
2. Although seroconversion seems to confer favorable outcomes in children with HBV
infection, Bortolotti et al. reported 2 cases of HCC, 9 and 16 years respectively after
seroconversion to anti-HBe . In our series, only 1 patient had histological signs of
cirrhosis, and none of the patients developed HCC .
3. There is no accurate standard for treatment of CHB in childhood: the age to undergo
treatment is not defined; the cut off value for HBV DNA and for transaminases in children
has not yet been established. When therapy is indicated, the preferred choice of therapeutic
agent is still not clear.
Page 6 of 9International Medical Press: Antiviral Therapy
4. Finally, studies of CHB management of children are also still limited. This resulted in lack
of information of the outcomes of different treatments in different conditions of the patients.
To date, it remains not well clear in which conditions should the children be treated or not. Thus,
careful understanding of the natural history of HBV infection and consideration of likelihood of
response and potential adverse events and the possibility of favorable spontaneous viral clearance is
needed before considering treatment of infected children.
Page 7 of 9 International Medical Press: Antiviral Therapy
1. Jonas MM, Block JM, Haber BA, et al. Hepatitis B Foundation. Treatment of children with
chronic hepatitis B virus infection in the United States: patient selection and therapeutic
options. Hepatology 2010;52:2192-05.
2. Iorio R, Giannattasio A, Cirillo F, et al. Long-term outcome in children with chronic
hepatitis B: a 24-year observation period. Clin Infect Dis 2007;15:943-49.
3. Bortolotti F, Guido M, Bartolacci S, et al. Chronic hepatitis B in children after e antigen
seroclearance: final report of a 29-year longitudinal study. Hepatology 2006;43:556-62.
4. Paganelli M, Stephenne X, Sokal EM. Chronic hepatitis B in children and adolescents. J
5. Hui CK, Leung N, Yuen ST, et al. Natural history and disease progression in Chinese
chronic hepatitis B patients in immune-tolerant phase. Hepatology 2007;46:395-01.
6. Iorio R, Verrico A, Giannattasio A. Is liver biopsy mandatory in children with chronic
hepatitis C? World J Gastroenterol 2007;13:4025-26.
7. Ovchinsky N, Moreira RK, Lefkowitch JH, et al. Liver biopsy in modern clinical practice: a
pediatric point-of-view. Adv Anat Pathol 2012;19:250-62.
8. Shamliyan TA, Johnson JR, MacDonald R, et al. Systematic review of the literature on
comparative effectiveness of antiviral treatments for chronic hepatitis B infection. J Gen
Intern Med 2011;26:326-39.
9. Manzat Saplacan RM, Mircea PA, Valean SD, et al. The long-term evolution of chronic
hepatitis B acquired in childhood. J Gastrointestin Liver Dis 2009;18:433-38.
10. Yuen MF, Lai CL. Natural history of chronic hepatitis B virus infection. J Gastroenterol
11. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic
hepatitis C virus infection: 2011 practice guideline by the American Association for the
Study of Liver Diseases. Hepatology 2011;54:1433-44.
Page 8 of 9 International Medical Press: Antiviral Therapy
12. Iorio R, Giannattasio A, Sepe A, et al. Chronic hepatitis C in childhood: an 18-year
experience. Clin Infect Dis 2005;41:1431-37.
Page 9 of 9International Medical Press: Antiviral Therapy