1999.11.3
昭和大学医学部 第二内科 柴田実
わが国では小児に対するIFN療法の適応が検討されておらず，限られた個人の経験に基づく証拠の質の低い議論が展開されているのが現状である．海外では小児に対するIFN療法はいくつかのRCT, meta-analysis, guidelineが報告されているので紹介する．
１．一番新しいMeta-analysisである．a long duration of treatment (12 months)が有効であると述べている．
Acta Gastroenterol Belg 1998 Apr-Jun;61(2):219-23
Interferon: a meta-analysis of published studies in pediatric chronic
hepatitis
B.
Vajro P, Migliaro F, Fontanella A, Orso G
Department of Pediatrics, University of Naples Federico II, Italy.
Perinatally infected Asian children respond poorly to interferon (IFN)
therapy.
In contrast, IFN therapy seems to be more effective in Caucasian children
who
presumably acquired HBV infection later in life. We reviewed seven
controlled
studies of IFN treatment in children with chronic hepatitis B living
in western
countries (216 treated, and 200 untreated children). Before treatment
all
patients were HBeAg and HBV-DNA +ve, with a biopsy proven chronic hepatitis
B.
Ages ranged 1 to 16 years (mean age 7 years). Most patients were Caucasian.
Protocols which have been adopted may schematically be divided into
protocols
which have used high doses of IFN (7.5 to 10 MU/sqm/TIW), and protocols
which
have used low doses of IFN (3 to 6 MU/sqm/TIW), with a short (3 to
6 months) or
a long duration of treatment (12 months). The percentage of treated
patients
who, at the end of treatment, lost HBV-DNA (that in most studies corresponded
also to HBeAg serum conversion) averages 20 to 58% (mean 35.5%) that
is much
higher than that observed in controls (range 8-17%; mean 11.4%). A
better trend
is probably observed only in patients who received the treatment for
a longer
period of time. At the end of treatment, low percentages of patients
lost BsAg
(range 0-4%; mean 1.1%): again higher doses tend to be more effective
than
lower doses. In some studies IFN has been shown to significantly accelerate
the
termination of viral replication. Data on longer term outcome of IFN
treatment
in Caucasian children are scarce and confirm results obtained at short
and at
medium-term FU either in horizontally either in perinatally infected
children.
Results from few randomized controlled trials of interferon therapy
with
prednisone priming in Chinese and Caucasian children were comparable
to results
obtained without prednisone. In one study steroid priming did not potentiate
the effect of IFN, however it existed a tendency of prednisone to improve
HBeAg
clearance in patients with normal aspartate aminotransferase, and alanine
aminotransferase activity lesser than 100 u/l. In most studies, factors
positively influencing response rates of IFN treatment are represented
by
severe inflammation in the basal liver biopsy, high basal levels of
serum
transaminase, low basal levels of serum HBV-DNA. Vertical transmission
may be
considered a factor adversely affecting the response to IFN treatment
both in
Chinese and Caucasian population. In general in most controlled studies,
the
majority of responders have shown a significant reduction in hepatic
inflammation and transaminase normalization. Children have a low risk
of
developing severe IFN-induced side effects. Adverse reactions and worsening
of
health-related quality of life were tolerable and did not seem to be
a limiting
factor for IFN therapy in young candidates.
Publication Types:
Meta-analysis
PMID: 9658614, UI: 98322750
２．文献１より２年ほど古いmeta-analysisである．IFN長期投与は有効であるが，IFNの高用量は有効に関係ないと述べています．
Clin Infect Dis 1996 Jul;23(1):131-7
Interferon-alpha therapy for chronic hepatitis B in children: a meta-analysis.
Torre D, Tambini R
Division of Infectious Diseases, Regional Hospital, Varese, Italy.
A meta-analysis of six randomized clinical trials involving 240 children
with
chronic hepatitis B treated with recombinant interferon-alpha (IFN-alpha)
was
performed. IFN-alpha treatment was effective in blocking viral replication.
Clearance of hepatitis B virus (HBV) DNA from sera occurred in 44 of
127
treated patients (P < .00001), and clearance of hepatitis B e antigen
(HBeAg)
occurred in seven of 74 treated patients (P = .099). IFN-alpha normalized
serum
levels of alanine aminotransferase (ALT) in 33 of 85 treated patients
(P =
.017). At the end of the follow-up period, viral replication was still
reduced
in IFN-alpha-treated patients, HBV DNA clearance occurred in 36 of
126 patients
(P = .014), and HBeAg clearance occurred in 29 of 126 patients (P =
.026).
Regarding these virological and biochemical endpoints, we found that
prolonged
therapy (> 6 months) was associated with a better response, whereas
high
dosages of IFN-alpha were not. These findings could be biased by limited
follow-up. Children with high ALT levels had a better response. However,
these
randomized clinical trials had some methodological flaws, including
the lack of
information on histologic response to IFN-alpha treatment by pediatric
patients
and the absence of "hard outcomes" (such as survival or development
of
cirrhosis or hepatocellular carcinoma).
Publication Types:
Meta-analysis
PMID: 8816142, UI: 96412896
３．小児のIFN療法のguidelineが報告されています．
J Pediatr Gastroenterol Nutr 1999 Aug;29(2):163-70
Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus
advice based on experience in European children.
Jara P, Bortolotti F
Hepatology Unit, Hospital Infantil La Paz, Madrid, Spain.
BACKGROUND: The efficacy of interferon (IFN) in children with chronic
hepatitis
B has been evaluated in randomized controlled trials over the past
decade, but
recommendations for treatment based on this experience have not been
published
yet. The purpose of this workshop, held in Madrid in October 1997,
was to
provide pediatricians with guidelines for practical use of IFN in hepatitis
B.
METHODS: Eighteen European pediatricians and hepatologists agreed to
report and
discuss their experience on 1,122 treated children, 40% of whom were
considered
responders. RESULTS: Agreement was obtained on the following main items:
1)
rationale for treatment is to accelerate hepatitis B early antigen
(HBeAg)
clearance in a subgroup of patients; 2) candidates for treatment are
children
with HBeAg and HBV DNA positivity, with low-intermediate HBV DNA levels
and
abnormal alanine aminotransferase values, aged 2 years or more; 3)
IFN is
contraindicated in children with decompensated liver disease, cytopenia,
severe
renal or cardiac disorders, and autoimmune disease; 4) the standard
treatment
regimen is 5 mU/m2 thrice weekly for 6 months. Retreatment in nonresponders
is
not indicated. CONCLUSIONS: A consensus was obtained on the use of
IFN in
children with hepatitis B, based on its short-term efficacy. The long-term
clinical and virological effects of the drug, however, remain to be
evaluated.
Publication Types:
Consensus development conference
Review
Comments:
Comment in: J Pediatr Gastroenterol Nutr 1999 Aug;29(2):125-6
PMID: 10435653, UI: 99362006
４? 最近の文献を以下に紹介します
Pediatr Infect Dis J 1999 Aug;18(8):694-7
Retreatment with higher dose interferon alpha in children with chronic
hepatitis B infection.
Ozen H, Kocak N, Yuce A, Gurakan F
Department of Pediatrics, Hacettepe University Ihsan Dogramaci Children's
Hospital, Ankara, Turkey. pedgastr@domi.com.tr
[Medline record in process]
BACKGROUND: More than 50% of children with chronic hepatitis B infection
do not
respond to interferon-alpha (IFN-alpha) treatment and are prone to
have
progressive liver disease. The best treatment modality is unknown in
these
children. The aim of this study was to evaluate the possible benefit
of a
second higher dose IFN-alpha therapy for children with chronic hepatitis
B
diseases who failed previous therapy. METHODS: Twenty-four children
with
chronic hepatitis B infection who had not responded to previous IFN-alpha
treatment were enrolled into the study. All were hepatitis B virus
DNA- and
hepatitis B e antigen-positive for >6 months after initial treatment.
They
received 10 megaunits (MU)/m2 of IFN-alpha 2a three times a week for
24 weeks.
Liver function tests, hepatitis B virus markers and hepatitis B virus
DNA were
determined regularly during treatment and follow-up. A complete response
was
defined as clearance of both hepatitis B virus DNA and hepatitis B
e antigen
(HBeAg). RESULTS: At the end of therapy 8 (33.3%) patients cleared
hepatitis B
virus DNA and seroconverted to anti-HBeAg. Patients were followed for
an
average period of 12.2 4.7 months after retreatment. During follow-up
an
additional 4 patients cleared hepatitis B virus DNA and seroconverted
to
anti-HBe, whereas one seroconverted patient became HBeAg-positive again.
Thus
11 patients (45.8%) had complete response at the end of the follow-up
period.
Alanine aminotransferase normalized in 11 responder patients and in
5
nonresponders. Positive predictive factors were low baseline titers
of
hepatitis B virus DNA and elevated transaminase values (> 100 IU/l).
CONCLUSIONS: IFN-alpha retreatment with a higher dose may be an alternative
modality for treatment of children with chronic hepatitis B infections
who
failed previous IFN-alpha, especially in those with favorable predictive
factors.
PMID: 10462338, UI: 99389434
----------
Eur J Pediatr 1998 May;157(5):382-5
Safety and efficacy of interferon retreatment in children with chronic
hepatitis B.
Ballauff A, Schneider T, Gerner P, Habermehl P, Behrens R, Wirth S
Department of Paediatrics, University of Essen, Germany.
More than 50% of children with chronic hepatitis B do not respond to
treatment
with alpha-interferon. Since these patients continue to display high
viral
replication and progressive liver disease, retreatment should be considered.
To
date it has not been well evaluated whether a second course of treatment
could
increase the response rate. In two alpha-interferon retreatment trials
in adult
patients the response rate, defined by seroconversion from HBeAg to
anti-HBe,
ranged between 11% and 44%. One beta-interferon retreatment study in
children
reported a seroconversion rate of 32%. Regrettably, none of the studies
included a control group observing the 'spontaneous' seroconversion
rate after
a first interferon cycle. Thus, a nonrandomized alpha-interferon retreatment
study in children including control patients was performed. Alpha-interferon
for retreatment was administered 3 times a week for 16-24 weeks in
15 children
(5-16 years) at least 6 months after ceasing the first cycle. Four
children
received 5 MU/m2 of a natural alpha-interferon and 11 children 9 MU/m2
recombinant alpha-interferon 2b. Follow up was 18-47 months after initial
treatment. In parallel, a control group of 19 unretreated children
with
comparable clinical and demographic data was followed for 12-39 months.
HBeAg
seroconversion was observed in 5 (33%) of the retreated children and
in 5 (26%)
of the control patients during follow up. The difference is not significant.
In
the initially nonresponding children, those with high ALT levels before
the
first treatment showed late HBeAg seroconversion more frequently than
those
with low ALT levels (P=0.017) irrespective of retreatment. The ALT
level before
retreatment was not a predictor for response. CONCLUSIONS: A second
cycle of
alpha-interferon during the 3 years following the first treatment in
nonresponding children with chronic hepatitis B can be safely performed
but did
not increase HBeAg/anti-HBe seroconversion compared with the spontaneous
seroconversion rate of patients without retreatment.
Publication Types:
Clinical trial
PMID: 9625334, UI: 98286998
----------
J Hepatol 1995;22(1 Suppl):49-51
Interferon treatment in children with chronic hepatitis B.
Ruiz-Moreno M
Department of Pediatrics, Fundacion Jimenez Diaz, Madrid, Spain.
Several trials for chronic hepatitis B in children have shown the usefulness
of
interferon-alpha (IFN-alpha) in eliminating hepatitis B virus (HBV)
replication, by an improvement in the liver damage. Optimal doses of
IFN-alpha
are 10 MU/m2 of body surface, three times a week for 24 weeks. With
this
schedule, clearance of HBV-DNA was achieved in 58% of treated children.
In
nonresponder children, because of the progression of the disease, there
is a
need to try new antiviral approaches. In a pilot study, 11 nonresponder
children were retreated with IFN-alpha 10 MU/m2 body surface, three
times a
week for 24 weeks. At the end of treatment, 27% of the children had
cleared
serum HBV-DNA. Thus, retreatment has some benefit in nonresponder children.
PMID: 7602077, UI: 95325564
----------
Am J Gastroenterol 1991 Mar;86(3):327-30
Prolonged treatment of children with chronic hepatitis B with recombinant
alpha
2a-interferon: a controlled, randomized study.
Utili R, Sagnelli E, Galanti B, Aprea L, Cesaro G, Digilio L, Filippini
P,
Felaco FM, Gaeta GB, Marrone A, et al
Institute of Medical Therapy, University of Naples First Medical School, Italy.
A prospective study was conducted to evaluate the efficacy and tolerance
of
alpha-interferon in 20 children with biopsy-proven
HBsAg/HBeAg/HBV-DNA-positive, anti-delta-negative chronic hepatitis.
Patients
were randomized to receive alpha 2a-interferon (INF), 3 MU im three
times
weekly for 12 months, or no treatment (10 patients per group). Five
patients
receiving IFN showed a marked decrease or negativization of HBV-DNA
during
treatment. At the end of the study (after 18 month), three patients
lost
HBV-DNA permanently, and two of them seroconverted to HBeAb 10 and
11 months
after disappearance of HBV-DNA with normalization of aminotransferase
values.
In the control group, one patient had spontaneous clearance of HBV-DNA
with
conversion to HBeAb and normalization of aminotransferase levels. All
treated
patients had a febrile reaction in the first month of treatment. The
dose of
IFN had to be decreased in two patients and was discontinued for persistent
intolerance in one of them. Patients who showed a decreased viral replication
had higher initial biochemical and histological activity than nonresponders.
The data suggest that IFN treatment may favorably influence the progression
of
chronic B hepatitis in children with a history of acute hepatitis and
active
chronic disease.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 1998314, UI: 91150732
----------