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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4046-4052
Dual or Single Hepatitis B and C Virus Infections in Childhood Cancer
Survivors: Long-Term Follow-Up and Effect of Interferon Treatment
By
Riccardo Utili,
Rosa Zampino,
Pasquale Bellopede,
Marta Marracino,
Enrico Ragone,
Luigi Elio Adinolfi,
Giuseppe Ruggiero,
Maria Capasso,
Paolo Indolfi,
Fiorina Casale,
Adele Martini, and
Maria Teresa Di
Tullio
From the Institute of Medical Therapy, Chair of Infectious Diseases,
Pediatric Oncologic Service, 2nd University of Naples,
Medical School, Naples, Italy.
 |
ABSTRACT |
We conducted a long-term prospective study of 89 cancer survivor
children who had acquired hepatitis B virus (HBV) and/or hepatitis C
virus (HCV) during treatment for neoplasia, the aim being to evaluate
the natural history of the diseases and the effect of interferon (IFN)
treatment. Patients were followed up for a median period of 13 years
(range, 8 to 20); 46 were infected by HBV, 11 by HCV, and 32 coinfected
by HBV and HCV. A spontaneous clearance of hepatitis B surface antigen
(HBsAg) occurred more frequently in coinfected patients
(19%) than in the HBV-infected (2%; P = .004), with an
annual seroconversion rate of 2.1% and 0.2%, respectively (P
= .008). Loss of hepatitis Be antigen (HBeAg) occurred in 44% of
coinfected and in 28% of HBV-infected patients. Clearance of serum
HCV-RNA was observed in 34% and 9%, respectively, of coinfected and
HCV-infected patients. Seventeen HBV-infected, 4 HCV-infected, and 16 coinfected patients received  -IFN treatment. In the HBV group,
6 patients (35%) cleared serum HBV DNA and seroconverted to anti-HBe;
in the HCV-group, none cleared HCV-RNA. In the coinfected group, 1 patient cleared both HBV DNA and HCV-RNA, 6 patients cleared serum
HCV-RNA alone, and 1 only HBV DNA and HBeAg. Overall, the diseases
showed a mild histological course with no evidence of liver cirrhosis.
A reciprocal interference on viral replication between HBV and
HCV may occur in coinfected patients. Treatment seems to be effective
for selected cases and is justified in view of the uncertain prognosis
of the disease in these patients.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
INFECTIONS BY HEPATITIS B virus
(HBV) or hepatitis C virus (HCV) acquired during infancy are
usually characterized by persistent viremia and a chronic mild
disease,1,2 although cases of childhood cirrhosis and
hepatocellular carcinoma (HCC) have been reported.1,3,4
During adolescence and even in adulthood, unsuccessful attempts by the
host to achieve viral immunoclearance (mainly in HBV patients) and/or
the high mutation rate of the viruses (mainly HCV) may lead to a
sustained necro-inflammatory activity and to progression to more severe
forms of liver disease.
In recent decades and, in particular, before the availability of
screening tests for HCV, children with oncological diseases were at
risk of acquiring the hepatitis viruses either as a single or as a
multiple infection. These viruses were acquired as a consequence of
transfusions of blood and blood products, of the direct exposure to
contaminated sanitary equipment, or to HBV or HCV carriers in the
hospital or the family environment at a time when the immune system was
markedly suppressed. Long-term studies of HBV or HCV infection in these
patients indicate the presence of a slowly progressive chronic liver
disease,5-7 but very little is known about patients with
HBV-HCV coinfection. In adults, coinfection appears to be more severe
than each infection alone.8
At present,  -interferon (IFN) is the only available treatment for
children with chronic HBV or HCV hepatitis. In HBV-infected white
children, the response rate to IFN is similar to that observed in
adults,9-11 whereas in HCV-infected children, the response rate has not yet been clearly established because it varies in relation
to viral and host factors.12-13 Very little is known about the efficacy of IFN treatment of chronic hepatitis acquired during a
previous oncological disease.5,14
Presently, in a prospective study, we are following up a group of
patients who were treated for malignancy during childood at the
Pediatric Oncologic Service, 2nd University of Naples, from
1978 to 1993, and were infected during this period by HBV and/or HCV.
In this report, we present the biochemical, virological, and
histological events of the infections during a long-term follow-up and
later the effects of IFN treatment.
| |
PATIENTS AND METHODS |
Study population.
Included in the study were consecutive children diagnosed and treated
for either leukemia/lymphoma or solid tumors who during treatment
showed an increase in serum aminotrasferases or the presence of
hepatitis B surface antigen (HBsAg) in serum. After 1990, all patients
were also tested for serum anti-HCV (anti-HCV) antibodies, and those
with a positive test were also included in the study. The exclusion
criteria from the study were the elevation of aminotrasferases and/or
positive HBsAg or, after 1990, anti-HCV in the serum at the time of
diagnosis of malignancy. For patients who acquired the neoplasia before
1990, we were unable to establish whether HCV infection was present
before malignancy. However, all HCV-infected patients had normal
alanine transaminase (ALT) at the time they started
chemotherapy and had had no obvious exposure to a potential source of
HCV infection.
Both during and after chemotherapy, liver function tests were evaluated
at 1 to 3 monthly intervals, as necessary, and serum viral markers
every 3 to 6 months.
After 1993, the patients were fully reevaluated for the progression of
liver disease and possible treatment. At this time, these patients
underwent a complete physical, biochemical, and virological examination
that included the determination of serum liver enzymes, markers of HBV,
HCV, hepatitis delta virus (HDV), and human immunodeficiency virus
(HIV), and, where indicated, serum HBV DNA and HCV-RNA. From this time
point, sera were stored at -70°C for subsequent determinations.
Quantitative serum HCV-RNA and HCV genotype were determined in all
HCV-RNA positive patients. All patients were also evaluated for thyroid
function and antinuclear, antimitochondrial, antismooth muscle, and
antiliver kidney microsome autoantibodies, as well as serum
ceruloplasmin, 1-antitrypsin, and ferritin. Serum liver enzymes were
routinely assessed every 3 months and markers of HBV replication
(hepatitis Be antigen [HBeAg], HBV DNA) every 6 months, while
qualitative and quantitative serum HCV-RNA were tested every year.
Liver and spleen doppler-ultrasound examination and serum
-fetoprotein assay were performed every year.
Histological evaluation.
All patients with elevated ALT (>1.5 upper normal levels
[UNL] in the preceding 6 months) and active viral
replication or with dual infection were considered for liver biopsy.
The pathological assessment was performed on sections from
formalin-fixed and paraffin-embedded liver biopsy stained with
hematoxylin-eosin, trichrome, and Prussian blue reaction. Histological
features were scored according to the Knodell Histological Activity
Index (HAI) and the Scheuer fibrosis score. We considered scores for
necro-inflammatory changes (grading) separately from architectural
alterations (staging).15
Treatment.
According to the current predictive criteria of a favorable response to
IFN,16-17 we decided to initiate treatment only in patients
with HBV or HCV replication and persistently elevated ALT in the last 6 months. Coinfected patients with replication of both viruses were also
treated. After the acquisition of informed consent, patients with HBV
infection or with dual HBV-HCV infection received -2a IFN (Roferon;
Roche, Basel, Switzerland), 5 megaunits (MU)/m2 3 times
weekly for 12 months, while those with HCV infection alone received 3 MU/m2 3 times weekly for 12 months. None of these patients
had been treated before with IFN. Treatment was discontinued after 6 months for nonresponder patients.
Response to treatment in the HBV group was defined on the basis of
serum HBV DNA and HBeAg clearance at the end of treatment and
seroconversion to the hepatitis B e antibody (anti-HBe) and ALT
normalization (ALT < 1.5 × UNL) within an additional 12 months. In the HCV group, response was defined on the basis of a sustained serum HCV-RNA negative test and ALT normalization at the end of therapy
and 12 months after suspension. In the HBV-HCV group, we considered the
anti-HBV and anti-HCV response separately. An increase in serum ALT and
return to a viremic status of either HBV (HBeAg and HBV DNA positive)
and/or HCV (HCV-RNA positive) was defined as a relapse after the
response to treatment.
Treated patients underwent clinical examination and routine laboratory
tests twice in the first month of treatment and every month until 6 months after the end of therapy and subsequently every 3 months. In
patients with HBV infection, markers of viral replication were tested
at months 2 and 6 of therapy and every 6 months thereafter. In patients
with HCV infection, viremia was studied before and at 6 and 12 months
of treatment and then every year. In untreated patients, biochemical
tests were performed every 3 months and virological determination every
6 to 12 months.
Virological markers.
HBsAg, HBeAg, anti-HBe, antidelta, and anti-HIV were tested in serum by
commercially available immunoenzymatic assays (EIA; Abbott
Laboratories, North Chicago, IL), anti-HCV by enzyme-linked immunosorbent assay (ELISA) II and III generation tests (Ortho Diagnostic System, Raritan, NJ). HBV DNA was assayed by liquid phase
hybridization (HBV DNA test, Abbott Laboratories); the sensitivity of
the test was 2 pg/mL. Anti-HCV were confirmed by Western blot (CHIRON
RIBA HCV 3.0; Chiron Co, Emeryville, CA). HCV-RNA was detected by
qualitative (PCR Hepatest C, ViennaLab, Vienna, Austria) and
quantitative b-DNA (Quantiplex, version 2, Chiron Co) tests. HCV
genotypes were determined by reverse hybridization line probe assay
(INNO LIPA HCV assay, 2nd generation; Innogenetics,
Zwijnaarde, Belgium).
Statistical analysis.
Statistical analysis of nonparametric data was performed using the
Fisher's exact test. Differences in viremia levels among the patient
groups were compared with the Mann-Whitney U test. Spontaneous
seroconversion rates to anti-HBe and anti-HBs were calculated and the
Kaplan-Meier life table method and Wilcoxon's and log rank sum tests
were used to compare the curves.18
| |
RESULTS |
According to the inclusion criteria, 89 patients from a total of 324 (27%) treated for malignancy acquired HBV and/or HCV infections during
treatment, 50 of whom were treated for solid tumor and 39 for leukemia
or lymphoma.
The median age of the patients when they entered the study was 4 years
(range, 1 to 16). On the basis of viral markers, patients were grouped
retrospectively as follows: 46 infected by HBV alone (HBV group), 11 by
HCV alone (HCV group), and 32 by HBV and HCV (HBV-HCV group). None of
these patients were infected by HDV or HIV.
During chemotherapy, 41%, 45%, and 81% of patients of HBV, HCV, and
HBV-HCV groups, respectively, showed biochemical evidence of acute
hepatitis. No patient developed signs of acute liver failure. The data
of patients on stopping chemotherapy are reported in
Table 1.
During a median follow-up of 13 years (range, 8 to 20) after stopping
chemotherapy, all patients remained asymptomatic with normal serum
bilirubin, albumin, and prothrombin times; all of them had normal
thyroid function tests and no evidence of autoimmunity or other
possible causes of chronic liver disease.
Analysis of HBV-infected patients.
After chemotherapy, all 46 patients were HBeAg positive, 26 with normal
and 20 with elevated ALT (Table 1).
During a median follow-up period of 12 years (range, 9 to 20), 13 patients (28%) cleared HBeAg spontaneously and showed a stable
seroconversion to anti-HBe (Fig 1). This
event occurred within 3 to 9 years (median, 6) after finishing
chemotherapy and was heralded by a transient and occasionally marked
elevation of ALT. One of these patients also seroconverted to anti-HBs
7 years after HBeAg clearance. In this group, the calculated mean annual rate of seroconversion to anti-HBe was 3.22% and to anti-HBs, 0.22%. An analysis of the conversion rates according to the
Kaplan-Meier life table is reported in Fig
2.
View larger version (22K):
[in this window]
[in a new window]
| Fig 2.
Cumulative probability of HBsAg (upper panel) and HBeAg
(lower panel) persistance in HBV-infected or HBV-HCV coinfected
patients during the follow-up (Kaplan-Meier method and log rank test).
NS, not significant.
|
|
Thirty-three patients showed active viral replication during the
follow-up (Fig 1). Patients with persistently normal ALT had a median
baseline serum HBV DNA of 273 pg/mL (range, 99 to 560) and those with
elevated ALT, 100 pg/mL (range, 5 to 405). All patients with elevated
ALT underwent liver biopsy. The median interval between end of
chemotherapy and liver biopsy was 9 years (range, 4 to 17). The
histological data are presented in Table 2.
Fifteen patients showed minimal changes, 6 mild chronic hepatitis, and
1 severe chronic hepatitis.
Of the 22 patients with a histological evaluation, 17 (9 males and 8 females, median age, 15; range, 7 to 24) were treated with -2a IFN.
Response to treatment is presented in Fig 1. Interestingly, the
pretreatment median serum HBV DNA level of the 7 responder patients was
25 pg/mL (range, 5 to 138), whereas that of nonresponders was 356 pg/mL
(range, 84 to 400; P = .002). Of the responder patients, 6 cleared HBV DNA and seroconverted to anti-HBe within the treatment period, and 1 seroconverted to anti-HBe within 12 months after suspending treatment. Anti-HBe seroconversion was associated with a
normalization of ALT. One patient had a relapse after the initial response to IFN.
Analysis of HCV-infected patients.
Eleven patients were found to be serum anti-HCV positive after
chemotherapy. No serum was available for HCV-RNA detection at the time
they discontinued chemotherapy. At the end of therapy, 4 patients had
normal ALT and 7 elevated ALT (Fig 3).
During the follow-up (median, 14 years; range, 9 to 20), 1 of the 4 patients with normal ALT showed constantly negative serum HCV-RNA over
a 9-year period (Fig 3). The other 3 patients had positive serum
HCV-RNA.
The 7 patients with elevated off-therapy ALT were serum HCV-RNA
positive during follow-up. Two showed a spontaneous biochemical remission over a period of 18 to 24 months, and 5 had persistent biochemical activity. In the 10 patients with positive serum HCV-RNA, the viral load ranged between < 0.2 to 0.7 × 106
Eq/mL (median, 0.34 × 106). No differences in the
viremia levels were observed between patients with normal and elevated
ALT. The HCV genotypes were analyzed in all HCV-RNA positive patients,
and the following distribution was observed: 1b, 6 patients; 2a/c, 2 patients; 3a, 1 patient; mixed 2a+1b, 1 patient.
A liver biopsy was performed for 4 of the 5 patients with biochemical
activity (for the fifth, both biopsy and IFN treatment were
contraindicated because of a psychiatric disorder) and in 1 with
persistently normal aminotransferases after a median follow-up period
of 13 years (range, 4 to 20) after stopping chemotherapy. Two patients
showed mild chronic hepatitis and 3 minimal changes (1 of the latter
was the patient with no biochemical activity). A median fibrosis score
of 1 was observed in all patients; the steatosis score ranged from 0 to
3 (Table 2).
The four patients with elevated ALT (all females, aged from 7 to 40 years) received IFN treatment. Of these, only 1 patient (genotype 1b,
baseline viral load 0.2 × 106 Eq/mL) showed an
end-treatment response, but relapsed shortly after stopping IFN.
Analysis of HBV-HCV-infected patients.
During chemotherapy, 32 patients proved to be infected by HBV and were
subsequently found to be also anti-HCV positive. Of the 26 patients who
presented evidence of acute hepatitis, 14 (54%) showed more than 1 peak of ALT elevation, which occurred at least 6 months apart. In this
period, 1 patient spontaneously cleared HBV infection and seroconverted
to anti-HBs. He normalized ALT and showed constantly negative serum
HCV-RNA during the entire follow-up.
During a median follow-up period of 14 years (range, 8 to 20), another
5 patients spontaneously seroconverted to anti-HBe and 1 also to
anti-HBs; they also cleared serum HCV-RNA and normalized ALT
(Fig 4). In addition, 8 patients cleared
HBeAg, but maintained HCV-RNA in the serum (4 of them also cleared HBV
infection and seroconverted to anti-HBs); 5 patients cleared HCV
viremia, but showed persistent HBV replication, and 13 still showed
active replication of both viruses (Fig 4).
Overall, a spontaneous recovery from HBV infection occurred in 19% of
coinfected patients versus 2% observed in the HBV-infected group
(P = . 04), the annual rate of HBsAg seroconversion being 2.1%
and 0.2%, respectively (P = .008; Fig 2). A spontaneous
clearance of HBV DNA with seroconversion to anti-HBe occurred in 44%
of coinfected patients at an annual rate of 5.1%. This prevalence, although higher, did not differ significantly from
those observed in the HBV group (Fig 2).
In HBV viremic patients, serum HBV DNA ranged from 5 to 470 pg/mL
(median, 129). Clearance of HBV DNA occurred between 3 months and 8 years after stopping chemotherapy. In the patients who cleared HBV
infection, anti-HBs seroconversion occurred 1 to 2 years after anti-HBe seroconversion.
The distribution of HCV genotypes in HCV-RNA positive patients was as
follows: 1b, 12 patients; 2a/c, 2 patients; 3a, 3 patients; mixed, 4 (1b+3a, 3 patients and 1a+1b, 1 patient) and serum HCV-RNA ranged from
<0.2 to 20 × 106 Eq/mL (median, 1.5 × 106). Overall, clearance of HCV-RNA occurred in 34% of
coinfected patients versus 9% of patients in the HCV-infected group
(P = .26)
Liver biopsy was performed in all 13 patients who presented replication
of both viruses, in 2 of the 5 with HBV replication alone, in 6 of the
8 with HCV replication alone, and in 2 of the subjects who had cleared
both viruses. The median interval between stopping chemotherapy and the
liver biopsy was 9 years (range, 3 to 14). The histological findings of
these 4 groups are reported in Table 2.
IFN therapy was administered to 12 of the 13 patients with replication
of both viruses, to 3 of the 8 with replication of HCV alone, and to 1 of the 5 with replication of HBV alone. At the end of treatment (Fig 4)
of the 12 treated patients with replication of both viruses, 1 showed
an anti-HBV and anti-HCV response that persisted 1 year later. Another
4 patients had a sustained anti-HCV response, whereas the HBV DNA serum
levels were unaffected by treatment, the mean levels being 241 pg/mL
before and 284 pg/mL 12 months after treatment. In these 4 patients,
ALT was constantly less than 1.5 × UNL. A sixth patient had an
anti-HBV, but not anti-HCV response and showed ALT normalization. The
serum HCV-RNA level was < 0.2 × 106 Eq/mL before
treatment and 0.3 × 106 after the clearance of HBeAg.
Furthermore, 2 of the 3 treated patients with HCV replication alone
cleared HCV-RNA and normalized ALT. The response to treatment was
sustained at 1 year follow-up. The 1 treated patient with HBV
replication alone showed no response to therapy (Fig 4).
The overall anti-HCV response was 47%. The responder patients had the
following HCV genotypes: 1b, 3 patients; 3a, 2 patients, mixed (1a+1b
and 1b+3a), 2 patients; their basal HCV viremia ranged from < 0.2 to
6.4 × 106 Eq/mL; median, 0.2 × 106
Eq/mL.
Side effects of IFN therapy.
Treatment was, in general, well-tolerated by the patients. A transient
influenza-like syndrome was observed in all treated children during the
first weeks of treatment. Only 1 patient, an 8-year old girl, had to
interrupt treatment after 5 months because of an episode of a febrile
convulsion. She had had a biochemical remission, but was still viremic
at the discontinuation of treatment. No patients showed evidence of
autoimmune disorders during treatment with IFN.
| |
DISCUSSION |
The acquisition of hepatitis viral infection by children treated for a
neoplastic disease represents a worrisome complication both for the
possible sequelae later in life and for the psychological implications
for the patients and their families, who are no sooner rid of a
life-threatening condition, than they find themselves facing a new and
potentially severe chronic illness. In our study population of children
with oncologic disease, the rate of HBV infection during chemotherapy
was 24% and that of HCV infection was 13%, although some HCV patients
who had cleared serum HCV RNA during chemotherapy and did not develop
elevated ALT or serum antibodies to HCV might have been
missed.6 The prevalence of HCV infection in our series is
similar to those reported by others,6,7 whereas that of HBV
is higher, which presumably reflects the high endemicity of HBV
infection in Southern Italy.19 It appeared that most HCV
infections were acquired via transfusion of blood or blood products,
whereas HBV infection was also acquired through other routes.
In recent published studies of children with a previous neoplasia who
had been infected by HBV and/or HCV,5-7 the disease showed
a benign course with no evidence of decompensation or of HCC over a
period of at least 10 years. However, despite the mild course of the
disease, histological evidence of cirrhosis was observed in 21% of
patients with HBV and HCV coinfection.7 In patients without
oncologic disease, HCV-HBV coinfection may be associated with a more
severe course of liver disease20,21 and to a higher risk of
fulminant hepatitis22,23 than the single HBV or HCV
infections. Furthermore, HBV integration in the host genome at an early
stage may predispose to the development of HCC.24 Thus, the
risk of HCC is higher in patients infected early on in life and is even
more elevated in patients with dual HBV-HCV infections.25
Our study showed variations in both the clinical presentation and the
course of HBV and/or HCV hepatitis when these viruses were acquired
during chemotherapy. In a substantial number of patients, the infection
showed no evidence of an acute disease and no subfulminant events
occurred. In the patients with a dual infection, the interval between
the 2 peaks of ALT elevation, when present, suggested sequential
infection by the 2 agents, rather than coinfection.
In accordance with other studies,5-7 we observed during a
long-term follow-up that for the majority of our patients, even those
with dual viremia, the disease ran a mild chronic course. None of the
patients developed severe fibrosis or cirrhosis during the follow-up.
The degree of histological lesions observed in our patients was similar
to those reported by others in HBV- and/or HCV-infected children
without oncologic disease.2,26
All of our cancer survivor children who acquired HBV alone appeared
unable to muster an effective antiviral immune response to HBV and
showed tolerance to the virus. In these subjects, the course of HBV
infection after stopping chemotherapy seemed to identify 2 different
cohorts of patients. The first showed a progressive restoration of the
immune response and spontaneously cleared HBV viremia (HBeAg clearance
rate, 28%). One of these patients also cleared the infection (HBsAg
clearance rate, 2%). In white children without oncologic disease with
chronic hepatitis B observed for a similar period of time, the reported
prevalence of HBeAg and HBsAg clearances is 84% and 3%,
respectively.2 The difference in the HBeAg seroconversion
most likely reflects the state of immunotolerance of our patients to HBV.
The second group of patients (72%) showed a persistent infection with
high viremia and a low histological and biochemical activity. The
latter features are associated with a low rate of spontaneous
seroconversion and arrest of viral replication.16
The long-term evaluation of pretreatment data seems to be important so
as to select patients with predictive factors of favorable response to
IFN. Indeed, if we consider all patients with HBV replication on the
basis of an intention-to-treat analysis, the therapeutic efficacy of
IFN treatment is 18%, whereas by optimizing the selection of patients
to treat,16 the observed response rate to IFN is 35%. A
similar prevalence has been reported in nonselected, white children
without oncologic disease.10,11,16 In addition to
pretreatment ALT, the baseline HBV DNA level has been confirmed as a
predictive factor of response to IFN.10,16
The acquisition of HCV infection by children with oncologic disease
during chemotherapy resulted in a HCV carrier state with minimal or
mild chronic histological damage. Approximately one third of these
patients showed no biochemical injury, but spontaneous recovery from
the infection was a rare event. The HCV genotype determination in both
HCV and HBV-HCV-infected patients showed a prevalence of type 1b,
reflecting the general distribution in our geographical
area.27 The low grade of histological injury was correlated
to the low levels of HCV viremia. No differences were found in the
genotype distribution or the HCV viral load between patients with
normal versus elevated ALT. None of the patients in this group
responded to IFN; the small number of patients treated does not,
however, allow any therapeutic considerations to be made. In
HCV-infected children without oncologic disease, the response to IFN
has been reported between 25% to 43%.12-13 The intrinsic
HCV genome resistance coupled with the immunotolerant state of our
patients might explain not only the mild form of hepatic disease, but
also the lack of response to IFN.
One of the most interesting aspects of our study emerges from the
observations of the HBV-HCV coinfected patients who showed a higher
number of spontaneous or IFN-induced virological events compared with
the groups of patients infected by either virus alone. This suggests
that mutual interference may occur between HBV and HCV.28
During chemotherapy, 1 patient apparently recovered from both HBV and
HCV infections. Moreover, after the discontinuation of chemotherapy, a
spontaneous recovery from HBV infection was significantly higher in
coinfected patients than in the HBV-infected. In our study, the annual
HBsAg seroconversion rate observed in coinfected patients (2.1%) was
not only higher than that observed in HBV-infected patients (0.2%),
but also than that reported in HBV-infected children without oncologic
disease (0.6%).29 A high clearance rate of HBsAg (29%) in
ex-oncological HBV-HCV coinfected children has also been reported by
Cesaro et al.7 Furthermore, coinfected patients tended to
show a higher prevalence of spontaneous seroconversion to anti-HBe.
These data suggest that HCV, when acquired as coinfection or as a
superinfection in chronic HBV carriers, seems to interfere with HBV and
may either attenuate its clinical presentation30 or
suppress the HBV replicative state.31
Interestingly, however, HBV may also influence the HCV replicative
state.32 As a spontaneous termination of HCV replication is
rare in children as it is in adults, it was interesting to observe the
greater tendency to clear serum HCV-RNA in patients with a dual HBV-HCV
infection compared with those with HCV infection alone.
The response to IFN treatment against HCV infection was different for
coinfected and singly infected patients. Although the small number of
patients treated did not allow a statistical significance to be reached
and caution should be applied in interpreting the data, it is
noteworthy that a sustained anti-HCV response to IFN occurred in 47%
of treated patients with dual infection as opposed to none of the
patients with HCV infection alone. The high response rate to HCV in
coinfected patients did not appear to be related to the more
susceptible genotypes of HCV or to lower viremia levels. Theoretically,
the difference in the anti-HCV response between coinfected and
HCV-infected patients might be due, at least in part, to the higher IFN
dosage received by coinfected patients, (5 v 3 MU/mq per dose).
However, the fact that the response was sustained in all responder
patients and that the response rate to HCV for coinfected patients is
higher than that reported in the literature for patients infected by
HCV alone in our area33 seems to suggest that other
factors, namely the presence of HBV in the replicative or in the
integrated state might have influenced the IFN-induced
arrest of HCV viremia.
It has been reported that the suppression of HCV replication induced by
IFN in HBV-HCV coinfected patients induced a reactivation of HBV
chronic hepatitis.34 Thus, the IFN-induced abrogation of
the putative suppressive effect of HCV on HBV might aggravate the HBV
disease. However, we observed no worsening of HBV replication or of ALT
levels in the 4 patients who showed an IFN-induced seroclearance of
HCV-RNA, but not of HBV DNA.
It was interesting to observe in our series that 1 patient had a
sustained favorable response to both HBV and HCV infection after IFN
treatment. This event has rarely been reported in the literature.35
The mechanism of the HCV-HBV mutual interference has not yet been
clarified and may involve an interplay of multiple cellular and
immunological factors, as well as the replicating processes of both
viruses.28 We may hypothesize that the impairment of the
immune response of patients at the time when they acquired both viruses
reduced the risk of a fatal outcome and caused a chronic indolent
course of the liver disease, with many patients (59%) losing either 1 or both viruses over time because of mutual viral interference.
In conclusion, hepatitis B and/or C infections acquired by children
during treatment for malignant disorders appear to have a mild course.
Long-term surveillance of these patients is warranted to verify whether
the recovery of the immune system after discontinuation of chemotherapy
may favor a spontaneous arrest of the replication of 1 or both viruses.
In patients who remain carriers of the viruses after 5 to 10 years, IFN
treatment may be indicated, as it does not appear to be harmful and may
be beneficial. The introduction of nucleoside analogues, ribavirin, and
lamivudine for HCV- and HBV-infected patients, respectively, may offer
new therapeutic options both for naive and nonresponder
patients.36-37 Ribavirin seems to increase the response
rate to IFN, whereas lamivudine may not only be better tolerated than
IFN, but also may be more effective because it is an antiviral and not
an immunomodulator drug. Although the importance of viral serum
clearance in the natural history of HBV and HCV infection has yet to be
established, we believe that any reasonable effort to eradicate the
infections in these children must be pursued because their long-term
outcome is still obscure.
| |
ACKNOWLEDGMENT |
The authors thank Geltrude Fiorillo for her valuable technical assistance.
| |
FOOTNOTES |
Submitted May 19, 1999; accepted August 18, 1999.
Supported in part by a grant from Ministero dell'Università e
della Ricerca Scientifica e Tecnologica, Italy, and in part, by a grant
from the Second University of Naples, Naples, Italy.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Professor Riccardo Utili, MD,
Istituto di Terapia Medica, 2° Università di Napoli, Via
Cotugno,1-(c/o Ospedale Gesù e Maria), 80135 Napoli, Italy;
e-mail: utili{at}unina.it.
| |
REFERENCES |
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Cryptogenetic chronic liver disease and hepatitis C virus infection in children.
J Hepatol
15:73, 1992
[Medline]
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