From Journal of Viral Hepatitis
Durability of Sustained Response Shown in Paediatric Patients With Chronic
Hepatitis C Who Were Treated With Interferon Alfa-2b Plus Ribavirin
D. A. Kelly; B. Haber; R. P. González-Peralta; K. F. Murray; M.
M. Jonas; J. P. Molleston; M. R. Narkewicz; F. R. Sinatra; T. Lang; A. Lachaux;
S. Wirth; M. Shelton; H. S. Te; H. Pollack; W. Deng; S. Noviello; J. K.
Albrecht
Source Medscape
Authors and Disclosures
Posted: 05/07/2012; J Viral Hepat. 2012;19(4):263-270. ©
2012 Blackwell Publishing
Abstract and Introduction
Abstract
Summary. Long-term studies in adults indicate that sustained virologic
response (SVR) after combination treatment for chronic hepatitis C (CHC)
predicts long-term clearance. Although peginterferon plus ribavirin is now
standard care for children with CHC, long-term follow-up studies are not yet
available. This study evaluated durability of virologic response over 5 years in
children previously treated with interferon alfa-2b plus ribavirin (IFN/R).
Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed
the 6-month follow-up in two previous clinical trials, participated in this
long-term follow-up study. All were assessed annually for up to 5 years;
patients with SVR were assessed for durability of virologic response. Children
with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA
24-week post-treatment (n = 41) were followed for a median of 284
weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One
patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with
the same genotype. Kaplan–Meier estimate for sustained response at 5 years was
98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels
(n = 4) or missing HCV RNA at the 24-week follow-up visit (n =
2) in the initial treatment studies had virologic response during this long-term
follow-up study. Linear growth rate was impaired during treatment with rapid
increases in the immediate 6 months post-treatment. Mean height percentile at
the end of the 5-year follow-up was slightly less than the mean pretreatment
height percentile. Five patients experienced serious adverse events; none
related to study drug exposure. SVR after IFN/R predicts long-term clearance of
HCV in paediatric patients; growth normalized in the majority of children during
the long-term follow-up. Similar long-term results could be expected after
peginterferon alfa-2b plus ribavirin treatment.
Introduction
The World Health Organization estimates the prevalence of hepatitis C virus
(HCV) infection between 1.3% and 1.7% in Europe and the Americas.[1]
Seroprevalence of HCV among children is lower than in adults, with
estimated rates of 0.1–0.4% in developed countries.[2,3] Although chronic hepatitis C
(CHC) is often benign in young children, the occurrence of fibrosis increases
with age and duration of the disease.[4] Thus, effective treatment of
children with CHC may reduce the progression of liver disease in young
adulthood.[5] Studies using interferon (both
nonpegylated and pegylated) plus ribavirin for 48 or 52 weeks in children and
adolescents with CHC have yielded sustained virologic response (SVR) rates of
46–65%.[6–11] However, the long-term safety
of interferon (both nonpegylated and pegylated) plus ribavirin and durability of
the virologic response in children are unknown and are essential outcome
measures.
In a long-term follow-up study of adults with CHC who attained SVR after
treatment with interferon alfa-2b with or without ribavirin, 99% remained virus
free during the subsequent 5-year period.[12] Similar findings were seen in
adults previously treated with peginterferon alfa-2b plus ribavirin.[13]
These findings indicate that sustained loss of serum HCV RNA for 6 months
after the end of treatment is an excellent predictor of long-term viral clearance in
adult patients with CHC.
The durability of response has not been formally studied in the paediatric
population. Although peginterferon plus ribavirin is currently the standard of
care for the treatment of paediatric patients with CHC, there are no long-term
data on safety or durability of virologic response. Thus, long-term data on
children treated with interferon alfa-2b plus ribavirin are uniquely relevant.
This study was designed to confirm long-term safety and durability of virologic
response in paediatric patients with CHC who were previously treated with
interferon alfa-2b plus ribavirin for 48 weeks.[8]
Materials and Methods
Study Design
A phase 3b, multicentre, long-term, follow-up study of paediatric patients
with CHC who were previously treated with interferon alfa-2b (Intron A®;
Schering-Plough Corporation, now Merck & Co., Whitehouse Station, NJ, USA) 3
MIU/m2 three times per week plus ribavirin
(Rebetol®; Schering-Plough Corporation, now Merck & Co.) 8, 12, or 15
mg/kg/day for 48 weeks in two international clinical trials was
conducted.[8] The initial treatment studies
allowed patients who had detectable HCV RNA levels at treatment week 24 to
discontinue as treatment failures at the discretion of individual investigators.
Patients who completed 24 weeks of follow-up after the end of treatment in the
two clinical trials were eligible for enrolment. No study medications were
administered to patients during the 5-year follow-up study.
Baseline data, including gastrointestinal/liver examinations, weight and
height measurements, haematology, blood chemistry, and HCV RNA, were obtained
from the 24-week follow-up visit in the initial treatment studies. Annual
assessments for clinical evidence of liver disease progression and safety in all
patients as well as virologic relapse in those who attained SVR in the initial
treatment studies were performed for up to 5 years. A patient was considered to
have an enduring SVR at a given time point if serum HCV RNA [by quantitative
polymerase chain reaction (PCR)] was undetectable at that time point. A patient
was considered to have relapsed if a single serum sample had detectable HCV
RNA.
Polymerase chain reaction testing for HCV RNA was performed by
Schering-Plough Research Institute using a proprietary TaqMan reverse
transcriptase–PCR assay (lower limit of detection, <125 IU/mL) and by Quest
Diagnostics, Nichols Institute, using the Roche COBAS TaqMan assay (lower limit
of quantitation, <50 IU/mL).
The study was conducted in accordance with Good Clinical Practice and was
approved by the appropriate institutional review boards and regulatory
agencies.
Study Population
Paediatric patients (3–16 years of age) from 24 study sites (17 in the United
States and seven international) who participated in one of two clinical trials
were invited to enrol in the long-term, follow-up study.[8] Patients who completed
24 weeks of follow-up in the initial treatment studies and whose parents or legal
guardians provided informed consent prior to any study-related procedures
were included.
Patients were excluded if they were currently participating in any other
clinical trial for treatment of CHC, if they had received antiviral retreatment
for CHC after completing 24 weeks of follow-up in the initial treatment studies
or if the investigator determined that the patient had any condition which would
make him or her unsuitable for participation in the study. Patients were
discontinued from the study if antiviral retreatment for CHC was administered,
if the investigator determined that it was in the best interest of the patient
or if the patient wished to withdraw.
Efficacy End Point
The primary efficacy end point was the assessment of the durability of SVR in
paediatric patients with CHC who were previously treated with interferon alfa-2b
plus ribavirin. Durability of SVR was assessed at 1 year after the week-24
follow-up visit of the initial treatment studies and then annually for the next
4 years.
Safety Assessments
Signs of clinical disease progression and safety were assessed for patients
at 1 year after the week-24 follow-up visit of the initial treatment studies and
then annually for the next 4 years. To assess for clinical disease progression,
investigators examined patients for ascites, hepatomegaly, splenomegaly and
liver tenderness. In addition to the physical exams and laboratory evaluations,
height and weight measurements were collected. Growth measurements were
converted electronically to an age- and gender-specific percentile according to
the method developed by the Centers for Disease Control and Prevention.[14]
Growth velocities during the different study
periods were compared with age- and gender-standardized norms for the US
population. Growth velocity was calculated by regressing assessed height during
the period over the day of assessed height from randomization. At least two
height assessments at least 90 days apart were required in any period to
calculate growth velocity. Growth velocity percentiles relative to those norms
were determined to assess the impact of treatment on growth.[14,15]
Results
Patient Disposition
Of the 166 patients who received interferon alfa-2b plus ribavirin in the two
initial treatment studies, 147 (78 sustained responders and 69 treatment
failures) completed 24 weeks of follow-up and were eligible for enrolment in the
long-term follow-up study (Fig. 1). Enrolled patients (N = 97) had been
treated with interferon alfa-2b (3 MIU/m2)
three times per week plus ribavirin 8 mg/kg/day (n = 11), 12 mg/kg/day
(n = 10) or 15 mg/kg/day (n = 76) at 16 study centres. Owing
to the timing of the initial treatment studies and long-term study enrolment,
the majority of the enrolled patients (54%, 52/97) were initially treated in the
second study, the phase 3 trial.[8] Of those enrolled in this
long-term follow-up study, 58% (56/97) had attained SVR and 42% (41/97) of them
had not attained SVR (Table 1). Therefore, 72% of sustained responders and
59% of treatment failures from the initial treatment studies entered this
long-term follow-up study. In genotype 1, infected patients were 77% (75/97) of
the study population, of whom 47% (35/75) had achieved SVR.
Figure 1.
Patient disposition. Study 1, a phase 1 trial, includes patients who were
treated with IFN alfa-2b plus RBV 8, 12 or 15 mg/kg/day and Study 2, a phase 3
trial, includes patients treated with IFN alfa-2b plus RBV 15
mg/kg/day.8
Duration of Long-term Follow-up
Overall, 70% (68/97) of patients completed the 5 years of long-term follow-up
(Table
2). More patients who attained SVR (75%, 42/56) than those who did
not attain SVR (63%, 26/41) in the initial treatment studies completed the
long-term follow-up. One patient with detectable HCV RNA at the end of the
initial treatment study was subsequently retreated with peginterferon alfa-2b
and ribavirin and was therefore withdrawn from the long-term follow-up
study.
Efficacy Evaluation
Durability of Response Of 56 patients who attained SVR, only one had
virologic relapse during long-term follow-up, with detectable serum HCV RNA
level of 3.6 million copies/mL at the year-1 annual evaluation. HCV genotype was
1a at initial infection and at relapse. This patient had received interferon
alfa-2b plus ribavirin (15 mg/kg/day) and completed 48 weeks of treatment
without any known dose reductions. The Kaplan–Meier point estimate (95%
confidence intervals) for the likelihood of maintaining SVR at 5 years after the
initial treatment studies was 98% (95%, 100%).
Alanine Aminotransferase Levels The majority (98%, 51/52) of patients
who attained SVR and had normal alanine aminotransferase (ALT) levels at the
24-week follow-up of the initial treatment studies maintained normal ALT levels
throughout their long-term follow-up visits. The remaining patient with SVR had
an elevated ALT level during long-term follow-up (67 U/L at the year-5 visit)
with hepatomegaly, possibly caused by obesity (body mass index of 37.1
kg/m2). The investigator did not consider this
finding to be clinically significant. In addition, three patients who attained
SVR but had abnormal ALT levels at week-24 follow-up visit had normalized ALT
levels at their last long-term follow-up evaluation. ALT values in the long-term
follow-up period were missing for one patient.
Treatment Failures Of the 41 patients who did not respond to therapy
and who had detectable HCV RNA levels at the 24-week follow-up in the initial
treatment studies, 26 (63%) completed the 5-year follow-up study. Among these 41
patients with treatment failure, 33 (80%) had ALT levels <2 times their
baseline ALT level throughout the study; 7 (17%) had elevated ALT levels of at
least two times their baseline level within the last 3 years of long-term
follow-up, despite having ALT levels <2 times their baseline level at the
24-week follow-up visit in the initial treatment studies; and one had missing
ALT levels.
Six patients who enrolled in the long-term follow-up study had been treated
with interferon alfa-2b (3 MIU/m2) three
times/week plus ribavirin 15 mg/kg/day in the initial treatment studies and were
classified as treatment failures. Four of these patients had low detectable
serum HCV RNA (125–250 copies/mL) at week-24 follow-up in the initial treatment
studies although they had undetectable HCV RNA levels at week 24 during
treatment and three of the four patients had undetectable HCV RNA levels at week
12 as well. These patients had undetectable serum HCV RNA and normal ALT values
throughout the long-term follow-up study (4–5 years after completing treatment).
The two remaining patients were defined as not having responded to therapy when
they entered the long-term follow-up study because, although they had
undetectable serum HCV RNA at their last visit in the initial treatment
protocol, they did not have HCV RNA results available for the 24-week follow-up
visit. However, their serum HCV RNA remained undetectable throughout the 5 years
of long-term follow-up.
Safety Evaluation
In this long-term follow-up study, 5% (5/97) of patients reported a serious
adverse event, all of which were considered unlikely to be related to previous
treatment with interferon alfa-2b and ribavirin. The serious adverse events
included a cardiac catheterization in a patient with a history of congenital
heart disease, injury with loss of consciousness after tipping an all-terrain
vehicle, contrast media reaction during magnetic resonance imaging, tooth
abscess and depression with self-injurious ideation and drug abuse after an
alleged sexual assault. No patients died during the study. During the initial
treatment studies, 23 of the 118 patients reported severe adverse events, which
included mainly neutropenia as well as more significant events of suicidal
ideation (n = 3), attempted suicide (n = 1) and hypothyroidism
requiring treatment (n = 3); one patient with hypothyroidism also
developed diabetes mellitus.[8] Of these seven patients with more
significant events, five patients were followed for up to 5 years in this
long-term follow-up study without further serious adverse events reported. Mean
changes in haematologic parameters (haemoglobin, platelet and white blood cell
counts) during treatment returned to normal levels at the end of the 24-week
follow-up period and remained stable during the long-term follow-up study. No
patient showed signs of clinical progression of hepatic disease.
Body Weight and Height During the initial treatment studies, weight
loss occurred during treatment with compensatory weight gain during the 24-week
follow-up and long-term follow-up (Table 3). The mean weight percentile, 60th
percentile, for all patients at the end of the long-term follow-up was above
their mean baseline weight percentile, 54th percentile, as well as the median
for the US population.[14]
The mean height percentile, 44th percentile, for all patients at the end of
the long-term follow-up was slightly below the patients' mean pretreatment
baseline height percentile, 48th percentile, and below the median for the US
population (Table
3). Twenty (21%) patients had >15 height percentiles decrease from
baseline to their last visit in the long-term follow-up period. Of these 20
patients, 10 patients had >30 percentiles decreases. Decreases in height of
>15 percentiles were most common in patients treated with interferon alfa-2b
plus ribavirin during their estimated period of peak growth velocity based on
age [girls 9–12 years old (6/15, 40%) vs girls 3–8 and 13–16 years old
(1/31, 3%); P = 0.001 and boys 11–14 years old (9/19, 47%) vs
boys 3–10 and 15–16 years old (4/32, 13%); P = 0.006]. In contrast, 15
(15%) patients (girls 4–12 years old and boys 5–16 years old) had increases in
height of >15 percentiles from baseline to their last visit in the long-term
follow-up study.
Mean growth velocity (2.46 ± 2.48 cm/year) and mean growth velocity
percentile (11 ± 22) were at their lowest during treatment (Table 3). During the 24-week follow-up period of the
initial studies, both growth velocity and growth velocity percentile increased
to levels above the median for the US population. Mean growth velocity during
this period was 5.40 ± 4.13 cm/year, and mean growth velocity percentile
increased to 62 ± 40. During the long-term follow-up period, mean growth
velocity was 3.29 ± 2.74 cm/year, and mean growth velocity percentile was 36.7 ±
37.6.
Discussion
Chronic hepatitis C is a significant cause of liver disease and a frequent
indication for liver transplantation in adults.[16] Long-term follow-up studies in
adult patients with CHC have shown that attainment of SVR (defined as
undetectable HCV RNA at 24 weeks after the end of therapy) following treatment
with interferon (nonpegylated and pegylated) with or without ribavirin therapy
is durable and predictive of long-term clinical benefit.[12,17–26] Results of this 5-year
follow-up study confirm that the long-term outcome for children who achieved SVR
with interferon alfa-2b and ribavirin treatment for CHC is consistent with that
observed in adults. Overall, 98% (55/56) of paediatric patients who attained SVR
maintained undetectable HCV RNA levels during the long-term follow-up period. In
addition to maintaining undetectable HCV RNA levels, 98% of paediatric patients
who attained SVR and had normal ALT levels following treatment maintained normal
ALT levels at their last long-term follow-up visit. The high percentage of
patients who maintained long-term undetectable HCV RNA levels and normalization
of ALT confirm the durability of virologic response in this population of
paediatric patients, highlighting the success of this therapy in children.
Although nonpegylated interferon plus ribavirin is no longer the standard of
care treatment for CHC in children, long-term data on safety and durability of
response of any interferon in this population are not yet available. This study
of long-term response in children treated with interferon alfa-2b plus ribavirin
demonstrates similar durability to that reported in adults and suggests that
similar outcomes are likely in children treated with peginterferon plus
ribavirin. In addition, this study provides data on decreases in growth during
combination therapy and recovery post-treatment, which is of value in selecting
children for CHC therapy.
The initial treatment studies indicated that 8% and 20% of patients had
haemoglobin level <10 g/dL and/or neutropenia (<1000 cells/L),
respectively, while on treatment they recovered to pretreatment levels after
therapy.[8] No evidence of latent effects of
treatment with interferon alfa-2b and ribavirin on haematologic parameters was
apparent. Additionally, no delayed serious adverse events related to previous
interferon alfa-2b and ribavirin treatment during the 5-year follow-up period
were reported.
Treatment with interferon alfa-2b has been shown to cause a temporary slowing
of growth in paediatric patients.[27] Growth analyses of the initial
and long-term follow-up studies showed that treatment with interferon alfa-2b
and ribavirin slowed patients' growth during treatment and that some patients
did not return to their baseline height percentile when treatment was completed.
The mean height percentile observed during the 5 years of follow-up was slightly
below the mean pretreatment height percentile and the median for the US
population, but the mean last weight percentile was above the median for the US
population and mean pretreatment weight percentile. Although the largest
decreases in height percentiles were mainly seen in patients treated during
their estimated peak height velocity based on age, there is much variability in
the timing and rate of growth during puberty between individuals, and growth
charts only capture a certain standard. In addition, a major limitation of our
observations regarding growth is the absence of parental height data that would
provide perspective on the patients' estimated final target heights.
Observations regarding a temporary reduction in growth velocity have also
been made in paediatric patients receiving peginterferon alfa-2b plus ribavirin.
Jara et al. reported a reduction in growth of 1.6 cm compared with the
growth velocity 50th percentile for age and sex in 22 of 26 paediatric patients
receiving peginterferon alfa-2b plus ribavirin. Despite a return to normal
growth velocity after the end of treatment, the authors reported that the modest
decrease in height percentile that occurred during treatment was not regained
during the 6-month follow-up period.[9] In addition, Wirth et
al.[10] reported that the mean height
percentile after the 24-week post-treatment follow-up period for 107 paediatric
patients treated with peginterferon alfa-2b plus ribavirin was slightly lower
than the median of the US population and below the mean pretreatment height
percentile. The 5-year long-term follow-up of this study is ongoing. However,
Sokal et al.[28] reported no influence of
peginterferon alfa-2a plus ribavirin therapy on height in 65 paediatric
patients. The trends seen in growth after interferon and ribavirin therapy are
not consistent.
The risk/benefit ratio between the possible slowing of growth in paediatric
patients receiving interferon products and the clinical consequences if
treatment is withheld or delayed must be considered when treating a child with
CHC with these agents. Much variability in growth was seen in this population,
but supporting data including parental heights, nutritional status, concurrent
disease status and medications were not available to firmly assess the impact of
treatment on growth in this population. The long-term effect on growth is being
further studied in patients who underwent treatment with peginterferon alfa-2b
and ribavirin, and will be available in coming years.
Spontaneous resolution of chronic HCV infection is rare in untreated
children, whereas persistent viremia after infection is almost universal.[5]
The disease course varies, but most children show
at least mild or moderate hepatic inflammation and a small proportion have
steatosis.[29] Rare cases of children with
hepatitis C-related bridging fibrosis, decompensated cirrhosis and
hepatocellular carcinoma have been reported.[4,30–33] Delaying therapy until early
adulthood may have less impact on growth but increases the risk of liver disease
progression or the need for liver transplantation in the interim, which may
impede attainment of SVR in later years. In contrast, early treatment with
interferon alfa-2b plus ribavirin results in an enduring clinical cure in almost
half of all treated paediatric patients. The possibility of successful viral
clearance needs to be weighed against the reported adverse events in children,
which are largely consistent with the well-described tolerability profile among
adult patients with hepatitis C receiving interferon alfa-2b (nonpegylated or
pegylated) plus ribavirin.[8] Thus, the arguments for
withholding therapy from paediatric patients may be outweighed by the benefits
of early viral eradication and the potential difficulties that may be incurred
if treatment is delayed until the course of disease is further advanced. In
addition, peginterferon alfa plus ribavirin treatment has shown improvement in
therapeutic outcome among paediatric patients with CHC and is likely to
demonstrate similar durability.[10,11]
In conclusion, results of this 5-year follow-up study confirm that sustained
loss of serum HCV RNA 24 weeks after the end of treatment with interferon
alfa-2b plus ribavirin is predictive of long-term virologic response in
paediatric patients. Most children had normalized (within 15 percentiles of
pretreatment height) or improved growth during this 5-year long-term follow-up,
although their mean height percentile at their last long-term follow-up visit
was slightly below their mean pretreatment height. The findings of this study
support the future treatment of paediatric patients with hepatitis C to prevent
progression of liver disease.
References
Overall, 70% (68/97) of patients completed the 5 years of long-term follow-up
(Table
2). More patients who attained SVR (75%, 42/56) than those who did
not attain SVR (63%, 26/41) in the initial treatment studies completed the
long-term follow-up. One patient with detectable HCV RNA at the end of the
initial treatment study was subsequently retreated with peginterferon alfa-2b
and ribavirin and was therefore withdrawn from the long-term follow-up
study.
Efficacy Evaluation
Durability of Response Of 56 patients who attained SVR, only one had
virologic relapse during long-term follow-up, with detectable serum HCV RNA
level of 3.6 million copies/mL at the year-1 annual evaluation. HCV genotype was
1a at initial infection and at relapse. This patient had received interferon
alfa-2b plus ribavirin (15 mg/kg/day) and completed 48 weeks of treatment
without any known dose reductions. The Kaplan–Meier point estimate (95%
confidence intervals) for the likelihood of maintaining SVR at 5 years after the
initial treatment studies was 98% (95%, 100%).
Alanine Aminotransferase Levels The majority (98%, 51/52) of patients
who attained SVR and had normal alanine aminotransferase (ALT) levels at the
24-week follow-up of the initial treatment studies maintained normal ALT levels
throughout their long-term follow-up visits. The remaining patient with SVR had
an elevated ALT level during long-term follow-up (67 U/L at the year-5 visit)
with hepatomegaly, possibly caused by obesity (body mass index of 37.1
kg/m2). The investigator did not consider this
finding to be clinically significant. In addition, three patients who attained
SVR but had abnormal ALT levels at week-24 follow-up visit had normalized ALT
levels at their last long-term follow-up evaluation. ALT values in the long-term
follow-up period were missing for one patient.
Treatment Failures Of the 41 patients who did not respond to therapy
and who had detectable HCV RNA levels at the 24-week follow-up in the initial
treatment studies, 26 (63%) completed the 5-year follow-up study. Among these 41
patients with treatment failure, 33 (80%) had ALT levels <2 times their
baseline ALT level throughout the study; 7 (17%) had elevated ALT levels of at
least two times their baseline level within the last 3 years of long-term
follow-up, despite having ALT levels <2 times their baseline level at the
24-week follow-up visit in the initial treatment studies; and one had missing
ALT levels.
Six patients who enrolled in the long-term follow-up study had been treated
with interferon alfa-2b (3 MIU/m2) three
times/week plus ribavirin 15 mg/kg/day in the initial treatment studies and were
classified as treatment failures. Four of these patients had low detectable
serum HCV RNA (125–250 copies/mL) at week-24 follow-up in the initial treatment
studies although they had undetectable HCV RNA levels at week 24 during
treatment and three of the four patients had undetectable HCV RNA levels at week
12 as well. These patients had undetectable serum HCV RNA and normal ALT values
throughout the long-term follow-up study (4–5 years after completing treatment).
The two remaining patients were defined as not having responded to therapy when
they entered the long-term follow-up study because, although they had
undetectable serum HCV RNA at their last visit in the initial treatment
protocol, they did not have HCV RNA results available for the 24-week follow-up
visit. However, their serum HCV RNA remained undetectable throughout the 5 years
of long-term follow-up.
Safety Evaluation
In this long-term follow-up study, 5% (5/97) of patients reported a serious
adverse event, all of which were considered unlikely to be related to previous
treatment with interferon alfa-2b and ribavirin. The serious adverse events
included a cardiac catheterization in a patient with a history of congenital
heart disease, injury with loss of consciousness after tipping an all-terrain
vehicle, contrast media reaction during magnetic resonance imaging, tooth
abscess and depression with self-injurious ideation and drug abuse after an
alleged sexual assault. No patients died during the study. During the initial
treatment studies, 23 of the 118 patients reported severe adverse events, which
included mainly neutropenia as well as more significant events of suicidal
ideation (n = 3), attempted suicide (n = 1) and hypothyroidism
requiring treatment (n = 3); one patient with hypothyroidism also
developed diabetes mellitus.[8] Of these seven patients with more
significant events, five patients were followed for up to 5 years in this
long-term follow-up study without further serious adverse events reported. Mean
changes in haematologic parameters (haemoglobin, platelet and white blood cell
counts) during treatment returned to normal levels at the end of the 24-week
follow-up period and remained stable during the long-term follow-up study. No
patient showed signs of clinical progression of hepatic disease.
Body Weight and Height During the initial treatment studies, weight
loss occurred during treatment with compensatory weight gain during the 24-week
follow-up and long-term follow-up (Table 3). The mean weight percentile, 60th
percentile, for all patients at the end of the long-term follow-up was above
their mean baseline weight percentile, 54th percentile, as well as the median
for the US population.[14]
The mean height percentile, 44th percentile, for all patients at the end of
the long-term follow-up was slightly below the patients' mean pretreatment
baseline height percentile, 48th percentile, and below the median for the US
population (Table
3). Twenty (21%) patients had >15 height percentiles decrease from
baseline to their last visit in the long-term follow-up period. Of these 20
patients, 10 patients had >30 percentiles decreases. Decreases in height of
>15 percentiles were most common in patients treated with interferon alfa-2b
plus ribavirin during their estimated period of peak growth velocity based on
age [girls 9–12 years old (6/15, 40%) vs girls 3–8 and 13–16 years old
(1/31, 3%); P = 0.001 and boys 11–14 years old (9/19, 47%) vs
boys 3–10 and 15–16 years old (4/32, 13%); P = 0.006]. In contrast, 15
(15%) patients (girls 4–12 years old and boys 5–16 years old) had increases in
height of >15 percentiles from baseline to their last visit in the long-term
follow-up study.
Mean growth velocity (2.46 ± 2.48 cm/year) and mean growth velocity
percentile (11 ± 22) were at their lowest during treatment (Table 3). During the 24-week follow-up period of the
initial studies, both growth velocity and growth velocity percentile increased
to levels above the median for the US population. Mean growth velocity during
this period was 5.40 ± 4.13 cm/year, and mean growth velocity percentile
increased to 62 ± 40. During the long-term follow-up period, mean growth
velocity was 3.29 ± 2.74 cm/year, and mean growth velocity percentile was 36.7 ±
37.6.
Discussion
Chronic hepatitis C is a significant cause of liver disease and a frequent
indication for liver transplantation in adults.[16] Long-term follow-up studies in
adult patients with CHC have shown that attainment of SVR (defined as
undetectable HCV RNA at 24 weeks after the end of therapy) following treatment
with interferon (nonpegylated and pegylated) with or without ribavirin therapy
is durable and predictive of long-term clinical benefit.[12,17–26] Results of this 5-year
follow-up study confirm that the long-term outcome for children who achieved SVR
with interferon alfa-2b and ribavirin treatment for CHC is consistent with that
observed in adults. Overall, 98% (55/56) of paediatric patients who attained SVR
maintained undetectable HCV RNA levels during the long-term follow-up period. In
addition to maintaining undetectable HCV RNA levels, 98% of paediatric patients
who attained SVR and had normal ALT levels following treatment maintained normal
ALT levels at their last long-term follow-up visit. The high percentage of
patients who maintained long-term undetectable HCV RNA levels and normalization
of ALT confirm the durability of virologic response in this population of
paediatric patients, highlighting the success of this therapy in children.
Although nonpegylated interferon plus ribavirin is no longer the standard of
care treatment for CHC in children, long-term data on safety and durability of
response of any interferon in this population are not yet available. This study
of long-term response in children treated with interferon alfa-2b plus ribavirin
demonstrates similar durability to that reported in adults and suggests that
similar outcomes are likely in children treated with peginterferon plus
ribavirin. In addition, this study provides data on decreases in growth during
combination therapy and recovery post-treatment, which is of value in selecting
children for CHC therapy.
The initial treatment studies indicated that 8% and 20% of patients had
haemoglobin level <10 g/dL and/or neutropenia (<1000 cells/L),
respectively, while on treatment they recovered to pretreatment levels after
therapy.[8] No evidence of latent effects of
treatment with interferon alfa-2b and ribavirin on haematologic parameters was
apparent. Additionally, no delayed serious adverse events related to previous
interferon alfa-2b and ribavirin treatment during the 5-year follow-up period
were reported.
Treatment with interferon alfa-2b has been shown to cause a temporary slowing
of growth in paediatric patients.[27] Growth analyses of the initial
and long-term follow-up studies showed that treatment with interferon alfa-2b
and ribavirin slowed patients' growth during treatment and that some patients
did not return to their baseline height percentile when treatment was completed.
The mean height percentile observed during the 5 years of follow-up was slightly
below the mean pretreatment height percentile and the median for the US
population, but the mean last weight percentile was above the median for the US
population and mean pretreatment weight percentile. Although the largest
decreases in height percentiles were mainly seen in patients treated during
their estimated peak height velocity based on age, there is much variability in
the timing and rate of growth during puberty between individuals, and growth
charts only capture a certain standard. In addition, a major limitation of our
observations regarding growth is the absence of parental height data that would
provide perspective on the patients' estimated final target heights.
Observations regarding a temporary reduction in growth velocity have also
been made in paediatric patients receiving peginterferon alfa-2b plus ribavirin.
Jara et al. reported a reduction in growth of 1.6 cm compared with the
growth velocity 50th percentile for age and sex in 22 of 26 paediatric patients
receiving peginterferon alfa-2b plus ribavirin. Despite a return to normal
growth velocity after the end of treatment, the authors reported that the modest
decrease in height percentile that occurred during treatment was not regained
during the 6-month follow-up period.[9] In addition, Wirth et
al.[10] reported that the mean height
percentile after the 24-week post-treatment follow-up period for 107 paediatric
patients treated with peginterferon alfa-2b plus ribavirin was slightly lower
than the median of the US population and below the mean pretreatment height
percentile. The 5-year long-term follow-up of this study is ongoing. However,
Sokal et al.[28] reported no influence of
peginterferon alfa-2a plus ribavirin therapy on height in 65 paediatric
patients. The trends seen in growth after interferon and ribavirin therapy are
not consistent.
The risk/benefit ratio between the possible slowing of growth in paediatric
patients receiving interferon products and the clinical consequences if
treatment is withheld or delayed must be considered when treating a child with
CHC with these agents. Much variability in growth was seen in this population,
but supporting data including parental heights, nutritional status, concurrent
disease status and medications were not available to firmly assess the impact of
treatment on growth in this population. The long-term effect on growth is being
further studied in patients who underwent treatment with peginterferon alfa-2b
and ribavirin, and will be available in coming years.
Spontaneous resolution of chronic HCV infection is rare in untreated
children, whereas persistent viremia after infection is almost universal.[5]
The disease course varies, but most children show
at least mild or moderate hepatic inflammation and a small proportion have
steatosis.[29] Rare cases of children with
hepatitis C-related bridging fibrosis, decompensated cirrhosis and
hepatocellular carcinoma have been reported.[4,30–33] Delaying therapy until early
adulthood may have less impact on growth but increases the risk of liver disease
progression or the need for liver transplantation in the interim, which may
impede attainment of SVR in later years. In contrast, early treatment with
interferon alfa-2b plus ribavirin results in an enduring clinical cure in almost
half of all treated paediatric patients. The possibility of successful viral
clearance needs to be weighed against the reported adverse events in children,
which are largely consistent with the well-described tolerability profile among
adult patients with hepatitis C receiving interferon alfa-2b (nonpegylated or
pegylated) plus ribavirin.[8] Thus, the arguments for
withholding therapy from paediatric patients may be outweighed by the benefits
of early viral eradication and the potential difficulties that may be incurred
if treatment is delayed until the course of disease is further advanced. In
addition, peginterferon alfa plus ribavirin treatment has shown improvement in
therapeutic outcome among paediatric patients with CHC and is likely to
demonstrate similar durability.[10,11]
In conclusion, results of this 5-year follow-up study confirm that sustained
loss of serum HCV RNA 24 weeks after the end of treatment with interferon
alfa-2b plus ribavirin is predictive of long-term virologic response in
paediatric patients. Most children had normalized (within 15 percentiles of
pretreatment height) or improved growth during this 5-year long-term follow-up,
although their mean height percentile at their last long-term follow-up visit
was slightly below their mean pretreatment height. The findings of this study
support the future treatment of paediatric patients with hepatitis C to prevent
progression of liver disease.
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