2013 Updates
Peginterferon/ribavirin effective for children, adolescents with chronic HCV

Updates 2012

Dec 2012
Medscape Medical News
Peg-Interferon Plus Ribavirin Safe and Effective in Children
Joe Barber Jr, PhD
Children and adolescents infected with hepatitis C virus (HCV) can be
safely and effectively treated with peg-interferon (PEG-IFN) in
combination with ribavirin (RBV), according to the findings of a meta-analysis
and review.      

Eric Druyts, MSc, from the University of Ottawa, Ontario, Canada, and
colleagues published their  findings online December 12 in Clinical Infectious Diseases.         

Despite the abundance of evidence supporting the efficacy of PEG-IFN and RBV
in the treatment of HCV infection in adults, the authors note that
the data supporting the use of this combination in children and adolescents are
sparse.

 "To date, only one RCT conducted among children and adolescents with HCV has
been presented in the published literature,"  the authors write.
"Comparable to those conduced in adult populations, this RCT found that the
combination of PEG-IFN alpha-2a  and RBV was superior to PEG-IFN
alpha-2a alone in those aged 5 to 17 years." 

In this study, the authors included 8 clinical trials that evaluated a full
course (typically 24 weeks for HCV genotypes 2/3  or 48 weeks for HCV
genotypes 1/4) of treatment with PEG-IFN alpha-2a or alpha-2b and RBV among
children and adolescents (aged  3 - 18 years) and presented data on
sustained virological responses (SVRs). Among the included studies, an SVR was
observed  in 58% (95% confidence interval [CI], 53% - 64%) of
participants and an early virological response was observed in 70% (95%         
CI, 58% - 81%) of patients.  

The authors excluded studies of patients coinfected with other viruses such
as HIV as well as observational studies and conference abstract data.
A sensitivity analysis revealed that the SVR and early virological response
rates were higher among patients  with genotypes 2/3 (89% [95% CI, 80%
- 96%] and 82% [95% CI, 68% - 92%], respectively) than among those with
genotypes 1/4  (52% [95% CI, 46% - 57%] and 64% [95% CI, 51% - 76%],
respectively).  

Relapse was observed in 7% (95% CI, 3% - 14%) of patients, and treatment
discontinuation because of a lack of virological  response to
treatment or to the reappearance of HCV RNA while receiving treatment was
observed in 15% (95% CI, 6% - 27%) and 4% (95% CI, 1% - 12%) of
patients, respectively.   

Although adverse events such as leukopenia (52%; 95% CI, 16% - 87%) and
neutropenia (32%; 95% CI, 22% - 44%) were common,  treatment
discontinuation because of adverse events was observed in only 4% (95% CI, 1% -
7%) of patients. Limitations of  the study include the small number of
analyzed studies, as well as only a single randomized controlled trial, the
differences  in treatment duration among the included studies, and the
inclusion of both treatment-naive and treatment-experienced patients           
in some trials.

 "The results of this meta-analysis indicate that [PEG-IFN] plus [RBV]
combination treatment is effective in treating children  and
adolescents with HCV," the authors conclude. "Although hematological and
dermatological adverse events are common, treatment discontinuations
due to these and other adverse events are infrequent." 

Two authors served as consultants with Merck & Co, Pfizer, Nycomed,
Takeda, Novartis, or GlaxoSmithKline. Druyts and the other authors have
disclosed no relevant financial relationships.
Clin Infect Dis. Published online December 12, 2012. 
View Abstract
Source - http://www.medscape.com/viewarticle/776843


Treatment of Chronic Hepatitis B and C in Children - Future Virology. 2012
HBV and HCV are the predominant causes of chronic viral hepatitis in children and adults. The main purposes of the present review are to provide the reader with a comprehensive overview of the currently available therapies for chronic hepatitis  B and C in children and to critically review the current guidelines and indications for treatment provided by the major international societies and by the consensus of expert panels. 

Overall, a conservative approach is generally warranted in children with chronic hepatitis B. For HCV, the high effectiveness of pegylated interferon and ribavirin in children with genotype 2 or 3 chronic infection  supports the decision to treat. For genotype 1 infection the encouraging results of the use of direct antiviral agents in adults suggest a more conservative approach.

Aug 8 2012
Height, weight and BMI changes seen in children treated with peginterferon alpha for hepatitis C

Hepatitis C Treatment May Hamper Kids’ GrowthLast Updated: August 13,  2012.
Study found weight returned to normal after peginterferon, but not  always height.
 
MONDAY, Aug. 13 (HealthDay News) -- Children with hepatitis C who are treated 
with peginterferon alpha may experience growth-related side effects from the 
therapy, a new study reveals.

 Although weight changes are reversible, many children's height for their age 
 may be lower even after the treatment for hepatitis C virus (HCV) ends, the 
 researchers found. 

The study was published in the August issue of Hepatology.

"While HCV in children is typically mild, some cases do progress to cirrhosis 
and liver cancer," lead study author Dr. Maureen Jonas, director of the Center 
for Childhood Liver Disease and medical director of the Liver Transplant
Program  at Boston Children's Hospital, said in a journal news release. 

"Treatment of HCV with peginterferon and ribavirin is approved for young 
children and offers the most benefit while liver disease is mild. However,
there  are concerns about the potential side effects of peginterferon therapy in 
children, which is the focus of our current study," Jonas explained.

The researchers followed 107 children (average age 11) with chronic hepatitis 
C, who participated in a study on the safety of hepatitis C treatments for an 
additional two years. Of these children, 55 percent were boys and 82 percent 
were white. When their treatment began, all of the children were of normal
height, weight and body mass index (BMI), a measurement that takes both weight 
and height into account.

The children were divided into three groups based on how long they were 
treated with peginterferon: 24, 48 or 72 weeks. The study found that while on 
the therapy, some of the children had decreases in height, weight, and BMI 
scores compared to standard scores. Moreover, 33 percent of the children on the 
therapy for 48 weeks showed even larger decreases in height-for-age scores.

Children who had been treated with peginterferon for 48 or 72 weeks had lower 
average height scores at the two-year follow-up point than when treatment
began.  The children's height-for-age scores did not rebound as quickly as their
weight  and BMI. However, the children's diet and level of physical activity had
not  changed over the course of the study.

"Additional investigation of growth patterns is needed to determine long-term 
outcomes so that optimal timing of treatment can be determined for children
with  chronic HCV," Jonas concluded.

Although the study found an association with peginterferon treatment and 
changes in children's growth patterns, it did not show a cause-and-effect  relationship.

July 29 2012
Hepatitis C In Children

June 2012
Diagnosis and Management of Hepatitis C Infection in Infants, Children, and Adolescents.
J Pediatr Gastroenterol Nutr, Volume 54, Number 6, June 2012

Autoimmunity and Extrahepatic Manifestations in Treatment-Naïve Children with Chronic Hepatitis C Virus Infection

MAY 7 2012
Durability of Sustained Response Shown in Paediatric Patients With Chronic  Hepatitis C Who Were Treated With Interferon Alfa-2b Plus Ribavirin

Mar 2012
Peginterferon for chronic hepatitis C in children affects growth and body composition: Results from the pediatric study of hepatitis C (PEDS-C) Trial
Hepatology.
2012 Mar 2. doi: 10.1002/hep.25690. [Epub ahead of print]
Jonas MM, Balistreri W, Gonzalez-Peralta RP, Haber B, Lobritto S, Mohan P, Molleston JP, Murray KF, Narkewicz MR, Rosenthal P, Schwarz KB, Barton BA, Shepherd JA, Mitchell PD, Duggan C; Hepatology (Mar 2012)

Background:
Weight loss and changes in growth are noted in children treated with interferonα. Objectives: To prospectively determine changes in weight, height, body mass index and body composition during and after treatment of children with hepatitis C. Methods: Children treated with PEG-IFNα(2a) +/- ribavirin in the PEDS-C trial underwent anthropometric measurements, DXA scan, dietary and activity assessments during and after treatment.

Results:
114 (55% male) children mean age 11±3 years were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into 3 groups according to duration of treatment: 24 (N=14), 48 (N=82), or 72 (N=11) weeks. Decrements of up to 0.50 z score were observed for weight, height and BMI while on therapy among all groups (P≤0.01 compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5 unit decrement in height-for-age Z score. While weight-for-age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post-therapy for the long treatment duration group (P=0.03) and lower than baseline in most children treated for 48 weeks.

Percent body fat, fat-free mass z scores and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment. Conclusions: PEG-IFNα(2a) was associated with significant changes in body weight, linear growth, body mass index and body composition in children. These effects were generally reversible with cessation of therapy, although height-for-age z scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV.
(HEPATOLOGY 2012.)
Source

Jan 2012

Current treatment options and response rates in children with chronic hepatitis C
World J Gastroenterol 2012 January 14; 18(2): 99-104
Download PDF
The prevalence of HCV in children in developed countries ranges between 0.1% and 0.4% but may even
exceed 10% in some regions of Saudi Arabia and Africa[6-8]. The rate of perinatal HCV transmission from an
infected mother to her child ranges from 2% to 5%. Clinically most relevant are genotypes 1, 2 and 3; considerably
less spread is genotype 4[2]. It is estimated that there are 1 million individuals aged less than 18 years infected with
chronic hepatitis C worldwide[9].

Treatment and follow up of children with chronic hepatitis C in Albania

Virtut Velmishi, Ermira Dervishi, Paskal Cullufi, Donjeta Bali and Vjollca Durro
Virology Journal 2012, 9:17 doi:10.1186/1743-422X-9-17

The complete article is available as a provisional PDF.
Published: 13 January 2012

Abstract (provisional)
Background

Treatment of Hepatitis C in children has a better outcome than in adults, and for this reason the treatment had different views. However, in pediatric age hepatitis C is seen to have an evolution towards chronicity. Today is a normal option to treat chronic hepatitis C as early as possible according to certain criteria.

The aim of this study is to show the results of treatment with interferon and ribavirin and the follow-up of children diagnosed with chronic hepatitis C in our service.

Patients and methods
This is a prospective study which has included children 3 up to 15 years old (13 boys and 4 girls) diagnosed with chronic hepatitis C. All patients underwent a certain protocol, including liver biopsy prior to treatment. Treatment consisted in use for 48 weeks of INF alpha-2b, 3 MIU/m2 three times a week s/c and ribavirin 15 mg / kg orally divided bid. Two patients were treated with PEGINF alpha-2b with dose 1.5 mcg / kg once a week s/c and ribavirin 15 mg / kg. After the treatment all patients have stayed under our control for an average period of 24 weeks.
 
Results
At the end of the treatment we detected a patient with HCV-RNA positive. End Treatment Viral Response was 94%. Six months later we found three patients who showed relapse of disease . Sustained Viral Response was approximately 83%

Conclusion
The combination therapy of interferon with Ribavirin in treatment of children with chronic hepatitis C provides a higher SVR when treatment is initiated at the earliest stages of hepatic changes. Side effects of therapy are insignificant in comparison with results obtained.

The complete article is available as a provisional PDF.
The fully formatted PDF and HTML versions are in production.


Dec 2011

Clinical prediction rule and platelet count predict esophageal varices in children
This month's issue of Gastroenterology identifies predictors of esophageal varices in children.

The validation of noninvasive tests to diagnose esophageal varices is a priority in children because repeated endoscopic evaluations are too invasive.

Dr Juan Cristóbal Gana and colleagues from Chile measured the ability of a previously developed noninvasive clinical prediction rule to predict the presence of esophageal varices in children.

The researchers analyzed data from 108 children, younger than age 18, who received endoscopies at 8 centers, to assess portal hypertension from chronic liver disease or portal vein obstruction.

Blood test and abdominal ultrasound scan results were obtained within 4 months of endoscopy.69% had esophageal varices

Gastroenterology
Grading of varices identified by endoscopy was confirmed by independent blinded review.Spleen size, based on data from the ultrasound scan, was expressed as a standard deviation score relative to normal values for age.

Of the children studied, 69% had esophageal varices, including 32% with large varices.The researchers observed that the best noninvasive predictors of esophageal varices of any size included platelet-to-spleen size z-score ratio, clinical prediction rule, and platelet count.

The research team found that positive predictive values for the clinical prediction rule, and platelet counts were 0.87 and 0.86, respectively.

The negative predictive values for clinical prediction rule and platelet counts were 0.64 and 0.63, the positive likelihood ratios were 3.06 and 2.76, and the negative likelihood ratios were 0.64 and 0.63, respectively.

The team observed that based on positive and negative predictive values, the most accurate noninvasive tests were the clinical prediction rule and platelet counts.

Dr Gana's team comments, "Noninvasive tests such as clinical prediction rule and platelet count can assist in triaging children for endoscopy to identify esophageal varices."Gastroenterol 2011: 141(6): 2009-201601 December 2011
Oct 17 2011

From Journal of Viral Hepatitis

Chronic Hepatitis C in Children

M. Abdel-Hady; S. K. Bunn; J. Sira; R. M. Brown; M. A. Brundler; P. Davies; D. A. Kelly

Authors and Disclosures

Posted: 10/17/2011; J Viral Hepat. 2011;18(10):e535-e540. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

The natural history of hepatitis C virus (HCV) infection in adults has been established, but less is known about outcome in children. We conducted a retrospective review of patients referred to Birmingham Children's Hospital Liver Unit, from 1991 till 2008, with the diagnosis of HCV was undertaken. Only children with documented positive HCV RNA and a minimum duration of follow-up of 6 months were included. One hundred and thirty-three children were identified. The route of transmission was transfusion acquired in 47%, vertically acquired in 49% and transplantation in 2%. Since 2000, most children were infected vertically. The overall rate of spontaneous viral clearance was 17.5% with higher clearance (27%) in the transfusion group compared to the vertically acquired group (9%). Seventy-six had a liver biopsy at diagnosis. There was no evidence of fibrosis in 46%, mild fibrosis in 50% and moderate to severe fibrosis in 4%. None had cirrhosis. There was a statistically significant relationship between fibrosis score and older age at the time of biopsy (P = 0.02) and longer duration of infection (P = 0.05). Eighty children received treatment for HCV. Sustained viral response (SVR) was influenced by viral genotypes, with significantly increased response rates in genotypes (G) 2 and 3 compared to G 1 and 4. Vertical infection is now the major route of HCV infection in children in the UK. Histological changes were mild at diagnosis, but the severity of fibrosis progressed with age. Consideration should be given to improve detection and diagnosis to refer children to specialist centres for management and antiviral therapy before developing fibrosis.

Introduction

The prevalence of the hepatitis C virus (HCV) is estimated to be between 0.4 and 1% of the UK population.[1] Since the discovery of HCV in 1989,[2] knowledge of the epidemiology, natural history and responsiveness of HCV to antiviral therapy has continued to accumulate.

In adults, HCV infection may lead to chronic hepatitis in about 80% of cases of which 5–15% may progress to liver cirrhosis over 20 years. Two to 5% of patients with liver cirrhosis will develop primary hepatocellular carcinoma.[3] In contrast, most children with HCV infection are asymptomatic and have mild histological findings.[4]

The aim of this study was to review the outcome of children with HCV at a national paediatric referral centre from 1991 to 2008.

Subjects and Methods

A retrospective case note review of all patients referred to Birmingham Children's Hospital Liver Unit, from December 1991 till December 2008, with the possible diagnosis of hepatitis C viral infection was undertaken. Only children with positive HCV RNA and a minimum duration of follow-up of 6 months were included. HCV RNA was detected by polymerase chain reaction using Roche Cobas Amplicor assay (Registration Status: CE-IVD; US-IVD; Canada-IVD, Roche, Pleasanton, CA, USA).

The age of infection was considered to be at the time of birth in vertically transmitted cases and for children who had acquired the infection in the neonatal period. In the transfusion-associated hepatitis C (TAC) group, the date of acquisition of infection is known in the group of children identified during the national HCV look-back programme. However, for the remaining cases of TAC, the time of infection was considered to be unknown.

Spontaneous viral clearance (SVC) of HCV was defined as natural clearance of HCV RNA documented at two consecutive tests 6 months apart. Liver biopsy was performed after informed consent either for disease staging or as a requirement prior to treatment. Fibrosis staging was scored using ISHAK score between 1990 and September 2004 and using METAVIR scores subsequently as a result of the change in the local reporting system. For the purpose of this review, staging was classified (Table 1).

Statistical Methods

Nonparametric methods of analysis were used as many of the variables considered were not normally distributed. Group comparisons of continuous variables were made by Mann–Whitney, Kruskal–Wallis or Jonckheere–Terpstra tests for trends over groups. Categorical data comparisons of groups were made using Chi-squared or Fisher's exact tests. Stepwise logistic regression was used to explore the influence of factors on the outcome of treatment.

All patients and families included in this study have consented for their data to be added to the National Hepatitis C Register and to be included in both national and hospital-based audits.[5]

Demography and Clinical Features

Between 1991 and 2008, 133 children with HCV were referred to the Liver Unit at Birmingham Children's Hospital. There were 79 boys (59%) and 54 girls (41%). The median age at referral was 7.4 years (range 0.5–18.7 years).

Mode of Infection

Of the 133 children referred, 63(47%) were infected via blood products (TAC), 65 (49%) with vertically acquired HCV infection (VAC) and 3 (2%) via infected transplantation. The mode of transmission was unknown in two cases, but based on their medical history, transmission was presumed to be through high-risk behaviour.

Transfusion-associated hepatitis C was the main cause for HCV infection in children referred between 1991 and 1995. However, this was superseded by VAC infection from 1995 onwards (Fig. 1).

Number of children referred to the liver unit at Birmingham Children's Hospital between 1991 and 2008 according to their mode of transmission. Transfusion-acquired hepatitis C (TAC) was the main mode of transmission till 2000. Vertically acquired hepatitis C (VAC) is the commonest mode of infection since 2000

Mode of Identification

Twenty-five (40%) children from TAC cases were identified via the look-back study.[6] Thirty-five (55%) were identified through 'risk group' screening (i.e. their HCV antibody status was checked because they had received blood product transfusions prior to 1991), and 3 (5%) children were identified after their transaminases were noted to be raised on routine blood testing.

Of the 65 VAC children, 24 (37%) were identified by following up babies born to HCV RNA-positive pregnant mothers, 24 (37%) by family screening after a sibling or mother was identified as being anti-HCV positive, 12 (18%) were identified on adoption screening and 5 (8%) were diagnosed following an incidental finding of raised serum transaminases. The mothers of the latter five children were subsequently identified as being anti-HCV positive. The route of infection in the mothers was intravenous drug use in 47 (72%), blood product infusion in ten (15%) and unknown in the remaining eight mothers (12%).

Spontaneous Viral Clearance

Twenty-three children who were HCV RNA positive at referral achieved SVC during follow-up. Therefore, SVC in the group as a whole was achieved in 17.5%, 17 (27%) of whom in the TAC group and 6 (9%) in the VAC group. None of the children became HCV RNA positive again over a median follow-up period of 4.6 years (0.5–11.5 years).

HCV Genotypes

Seventy-two children (63%) were genotype 1, 3 (3%) were genotype 2, 37 (33%) were genotype 3 and 2 were genotype 4. There was no noteworthy association between genotype and mode of infection.

Liver Function

At presentation, the median (range) transaminases for the VAC group were ALT 51 (12–300) and AST 52 (15–158) and for the TAC group were ALT 56.5 (14–877) and AST 47.5 (22–230) with no significant difference between the two groups (P = 0.84 and P = 0.64, respectively).

There was no significant difference in ALT but a statistically significant difference in AST between those children who were HCV RNA negative (spontaneously cleared the virus), ALT 39 (22–86) and AST 37 (22–46), and those who were HCVRNA positive (chronically infected), ALT 54 (12–877) and AST 53 (15–230) (P = 0.20 and P = 0.023, respectively).

Histology

Seventy-six children had at least one liver biopsy performed either for disease staging or as a requirement prior to a therapeutic trial. Fifteen children had two biopsies and three children had three biopsies available for review. Fibrosis was staged using the ISHAK score in 47 cases and the METAVIR score in 29 cases.

There was no evidence of fibrosis in 35 cases (46%), mild fibrosis in 38 (50%) and the remaining 3 (4%) had moderate to severe fibrosis. None of the cases had documented cirrhosis. The median age at the time of the biopsy was 6.3 years for the group with no fibrosis, compared to 10.1 years in the group with moderate to severe fibrosis. There was a statistically significant relationship (rank correlation 0.29, P = 0.02, Jonckheere–Terpstra test) between fibrosis score and the age at time of biopsy. A similar pattern was detected between fibrosis score and duration of infection (rank correlation 0.40, P = 0.05, Jonckheere–Terpstra test) (Fig. 2).

Relationship between fibrosis, score and age at time of biopsy/duration of infection. There was a statistically significant relationship between fibrosis score and age at biopsy and duration of infection (P = 0.02, P = 0.05 Jonckheere–Terpstra test, respectively).

With regard to mode of transmission, 56% in the VAC group had no fibrosis in their liver biopsies compared with 26% in the TAC groups (P = 0.01). The mean age at the time of biopsy was 6.3 years in the VAC children and 12.6 years in the other group.

There were 15 children who had more than one liver biopsy. The median time between the first and the second biopsy was 39 months (range 12–122 months). The median change in fibrotic stage between first and most recent biopsy was 0 (range − to +1), as eight of the 15 children showed no fibrosis progression between biopsies and six had progression of fibrosis by one stage. One had fibrosis score 2 on first biopsy and score 1 on second biopsy using the ISHAK scoring on both occasions.

Treatment

Eighty children have received treatment for hepatitis C of whom 17 were treated with interferon α2a alone, and 18 received a combination of interferon and ribavirin.[7] Forty-five were treated with pegylated interferon α2a (PEG-IFN α2a) and ribavirin, 18/45 were treated as part of a clinical trial (CHIPS)[8] and 27 according to our current local management protocol with PEG-IFN α2a (100 μcg/m2) and ribavirin (15 mg/kg/day) for 48 weeks in genotype 1 and 24 weeks in genotypes 2 and 3.

Sustained viral response (SVR), as defined by negative HCV RNA 24 weeks following treatment, was achieved in 12% in the group treated with interferon monotherapy. Higher SVR rate was documented in the groups treated with combination therapy of IFN and ribavirin (52%) or PEG-IFN and ribavirin (73%).

There was no significant difference between treatment outcome in VAC and TAC groups treated with interferon and ribavirin, P = 0.77, or treated with PEG-IFN and ribavirin P = 0.93 (Table 2).

Applying logistic regression analysis to evaluate factors affecting treatment outcomes, SVR is largely affected by viral genotypes, with significantly increased response rates in G2 and G3 compared to G1 and 4, [P = 0.006 and OR 8.7,95%CI (1.9–40.2)]. On the other hand, there was no significant effect of the drug type used (IFN and ribavirin compared to PEG-IFN and ribavirin) P = 0.94. Although the VAC group had slightly better response rate compared to TAC group, this was not statistically significant [P = 0.24, OR 0.39; 95% CI (0.08–1.89)].

Median age at starting treatment was 9.9 years (range 3.0–19.6 years) for the group as a whole, 13.7 years in the TAC group and 7.3 in the VAC cases. The median age at starting treatment in the responders was 8.4 years and 12.7 years in the nonresponders.

Discussion

In this study, we describe our experience in the management of children and adolescents with HCV in a national paediatric liver unit in the UK over a 17-year period. The number of referrals peaked in 1995 because of retrospective surveillance as part of the 'look-back' study.[6]

In this study, there has been a consistent rise in the number of children referred with vertically acquired HCV from 1995 and has been the commonest mode of infection in the studied cohort since 2000. The only cases referred to our centre with transfusion-acquired HCV after 2003 have received their transfusion abroad. These findings are in concordance with other reports from countries that have screened donated blood for HCV since the early 1990s.[9,10]

It is estimated that there are 1150 HCV-infected pregnant women in the UK per year [a prevalence of 0·16% (0·09–0·25%)].[11] The estimated rate of vertical HCV transmission ranges from 2 to 5%, with the risk of vertical transmission increasing with a traumatic vaginal delivery, high maternal viral load at the time of birth and maternal HIV co-infection.[12–14]

The above-reported prevalence and transmission rate suggest an estimate of approximately 70 new paediatric HCV VAC infections per year.[15,16] Nevertheless, there were only 65 referrals to our centre in over 17 years, implying either that not all infected mothers and children are being identified, or they are being cared for in different units. Additionally, only 37% of those referred were identified by planned follow-up because the mother was known to be HCV positive antenatally. This highlights the degree of under-diagnosis of vertically transmitted HCV in the UK. Antenatal HCV screening is not currently part of the national routine screening programme in the UK because it was felt vertical transmission could not be prevented.[17] However, the development of effective therapy for HCV means that it is important to detect and treat HCV-infected mothers and children, particularly those with genotypes 2 and 3.[18]

The rate of SVC overall in our study was 17.5% with 27% clearance rate in the TAC group. Similar results were reported in other studies[19,20] with SVC rates of 27.6% in TAC and 28.6% in 56 TAC patients who had survived childhood leukaemia. Other studies[21,22] have reported higher SVC rates in transfusion-acquired HCV, 45% and 35%, respectively.

In contrast, SVC rate of VAC-infected children in this study was 9%. Higher SVC rates (19%, 21–25%) were reported in other studies.[4,18] These data are in contrast with previous authors who did not find a difference in SVC and mode of transmission.[19,23]

It is not clear why there is such a difference in SVC, but poorer SVC rates for the VAC group may be a reflection of an immature immune system at the time of acquiring the infection or the development of immunotolerance, as occurs with hepatitis B. This suggestion is supported by data showing that children who are immunosuppressed at the time of blood product infection with HCV had a lower SVC rate.[24–26]

Alternatively, it is not clear whether age at infection influences SVC rates. In a study involving 712 HCV antibody-positive haemophiliacs, 27% spontaneously cleared HCV but this was higher if infected when young, especially if infected at <2 years of age.[27]

In this study, 96% of the biopsies reviewed had no or mild fibrosis. Similar results were reported in other studies.[28–30] Furthermore, the results of a European multicentre study of 224 paediatric patients with chronic hepatitis HCV showed that only 2% of children are likely to develop cirrhosis.[31]

In childhood, fibrosis is a slow progressive process; hence, its severity relates to the duration of infection. Progression of fibrosis with time does not appear to be linear; therefore, severity of fibrosis is not a reliable prognostic indicator.[32]

Within our group, there was a clear relationship between the degree of fibrosis and the child's age at biopsy and the duration of infection. This finding was reported in other studies.[21,33]

In this study, there were significantly more children in the VAC group with fibrosis absent compared to those in the TAC group, P = 0.027. This is likely to be a result of younger age at the time of biopsy in this group (median age 6.3 years) compared to the TAC group (median age 12.6 years) but could also reflect the absence of co-morbidities in the VAC group. In other paediatric studies, there was no correlation between the route of transmission and the stage of fibrosis.[32,34]

Hepatitis C in children has a less aggressive course with low rate of fibrosis formation compared to adults infected for the same length of time. The reduced frequency of co-morbid factors such as alcohol consumption, haemochromatosis and nonalcoholic fatty liver disease in children may account for this less aggressive course.[9]

Treatment of hepatitis C is challenging requiring combination drugs used for 6–12 months with significant side effects and toxicity. However, paediatric trials have shown these drugs to be safe and effective when used in specialized centres under close supervision, especially for those infected with genotype 2 and genotype 3.[7]

In our study, we document the steady improvement with new therapy. The main factor affecting treatment outcome was genotype with significantly higher response rate in G2 and 3 compared to G1 and 4 as previously reported.[8,35]

Recognizing the failure of selective antenatal screening for HCV and the availability of an effective treatment raises the question as to whether universal antenatal screening for HCV should be promoted, especially in the light of low spontaneous viral clearance rates, potential prolonged length of infection and fibrosis progression with age in perinatally infected children.

Conclusion

We demonstrate the changing epidemiology of hepatitis C in children in the UK. The major route of infection of HCV in children is now vertical transmission, and these children are less likely to clear the infection spontaneously but respond well to treatment at a younger age before fibrosis develops. Only one-third were identified through selective antenatal screening suggesting that there may be many unidentified perinatally infected children in the UK in the absence of routine maternal antenatal screening.

Most children are asymptomatic with mildly abnormal hepatic transaminases. Histological damage is mild in childhood, but the extent of fibrosis correlates with age and progresses with time; therefore, continuous monitoring of infected paediatric patients is recommended with early consideration for the treatment before fibrosis develops.

Hepatitis C is a rare condition in children in the UK but as treatment opportunities increase, consideration should be given to early detection and referral to specialist units for information, counselling and treatment. 

• References

Pediatric hepatitis C infection: to treat or not to treat…what’s the best for the child?

D. Serranti, D. Buonsenso, M. Ceccarelli, L. Gargiullo, O. Ranno, P. Valentini
Department of Pediatrics, School of Medicine, Catholic University of the Sacred Heart, Rome (Italy)
Paediatrics and Infectious Disease

Abstract. – Objectives: Pediatric hepatitis C mainly occurs through mother to child transmission, to date. Children usually present a mild disease, but they are not spared from its long-term complications. Thus this infection cannot be underestimated in children and intervention is necessary. Current treatment is based on the administration of pegylated-interferon associated with ribavirin, but few studies evaluated the efficacy and safety of this therapeutic protocol. Moreover, there is still no clarity on who, when and how to treat pediatric patients. This article, based on the information in literature, provides an overview of the main aspects of the disease, with particular attention to treatment.

Methodology and Results: We describe the different treatment options available. About the association peginterferon plus ribavirin, we analyze thirteen non-randomized studies and one trial, found in recent literature. These studies are not directly compared because of differences in age, type of infection (vertical or not), viral genotypes and duration of treatment, between groups enrolled. The overall sustained viral response rate ranges from 28.6% to 81.8%. The rate of treatment success is higher in children infected with genotypes 2 and 3 than with other genotypes. The therapy does not induce severe adverse effects and children present better tolerance to antiviral than adults.

Conclusions: The pharmacological efficacy of peginterferon and ribavirin seems to be proven by data collected in studies cited, but there are different opinions about who, when and how to treat children infected. Thus, further research is needed to define the best management of vertical acquired hepatitis C.


Pediatric Infectious Disease Journal: September 2011 - Volume 30
Issue 9 - pp 801-804 doi: 10.1097/INF.0b013e3182196ab4
Brief Reports
Impact of Human Immunodeficiency Virus Coinfection on the Progression of Mother-to-child Transmitted Hepatitis C Virus
 Infection

Claret-Teruel, Gemma MD, PhD*; Noguera-Julian, Antoni MD, PhD*; Esteva, Cristina BSc†; Muñoz-Almagro, Carmen MD, PhD†; Sánchez, Emília MD, PhD‡; Jiménez, Rafael MD, PhD*; Fortuny, Clàudia MD, PhD*

Abstract
Data on mother-to-child transmitted human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection are scarce. A prospective observational study with a cohort of 70 HCV-infected children (13 of whom were HIV/HCV-coinfected; mean follow-up: 7.3 years) is presented. In our series, surrogate markers of disease progression (HCV viremia, maximum alanine aminotransferase values, and spontaneous HCV infection clearance) suggest that the evolution of liver disease in HIV/HCV-coinfected pediatric patients is more aggressive than it is in HCV-only infected children.


Treating Hepatitis C In Children

Aug 2011

From Journal of Viral Hepatitis
The Impact of Mode of Acquisition on Biological Markers of Paediatric Hepatitis C Virus Infection
K. England; C. Thorne; H. Harris; M. Ramsay; M.-L. Newell
Authors and Disclosures
Posted: 08/29/2011; J Viral Hepat. 2011;18(8):533-541.
© 2011 Blackwell Publishing

Discussion Only;
The impact of mode of acquisition on biological markers of HCV infection in the largest comparison of vertically and parenterally infected children to date was investigated. A significantly higher mean ALT z-score in vertically vs parenterally infected and a significantly higher mean ALT z-score in children infected before 12 months of age, regardless of mode of acquisition, was found. This latter association did not remain when only parenterally infected children were investigated which may be because of small numbers but may also indicate that the differences between groups are not completely explained by age at infection but may be related more directly to the mode of acquisition of infection itself.

Comparing biological markers of HCV infection in vertically and parenterally infected children is problematic in the light of the often substantial differences in populations in terms of age at infection, age at study entry, treatment profile, likelihood of clearance of viraemia or genotype. In the children from the cohorts studied here, four times as many parenterally than vertically infected children received HCV treatment; this may be because of more severe disease in parenterally infected children because of their age or mode of acquisition, as suggested by the finding here of a higher proportion with two or more markers of disease progression. Alternatively, their older age at diagnosis may make them more eligible for the treatment while vertically infected children, who were followed from birth, will have started on a regime of clinical monitoring without treatment. Although HCV therapy is well adhered to in the paediatric population, the unpleasant side effects and the potential impact on growth make the decision to treat a complex one.[18] There could also be bias in terms of the individual clinic or national treatment policies, especially given the continually evolving nature of information on paediatric HCV treatment and the ongoing debate about when to initiate treatment.[19]

This debate on when to initiate treatment is partly fuelled by knowledge that some children spontaneously clear viraemia without treatment. In this study, there was no effect of mode of acquisition on clearance of viraemia in contrast to some previous studies.[20] However, parenterally infected children in the UK National HCV Register were not followed up from the time of infection and possibly a large number of those who cleared viraemia did so before diagnosis or study entry. Therefore, any estimate of clearance here and elsewhere, likely underestimates the true proportion clearing viraemia in parenterally infected groups. Of note, however, the high clearance rates in parenterally infected groups are reported in this and other studies[9,21,22] which would presumably be even higher if those who cleared viraemia prior to diagnosis could be included. It may therefore be the case that parenterally infected children are more likely to clear the virus than vertically infected children but it is unlikely that this can be substantiated as follow-up from infection in parenterally infected children is rare.

No differences were found in the HCV genotype profiles of vertically and parenterally infected children in contrast to Jara et al. who found genotype 1b more frequently in children with transfusion-acquired HCV and genotype 3 more frequently in vertically infected children from seven European countries.[23] It is possible that this is because of differences in the years at which infection occurred and may reflect changes in the genotype profile of the HCV epidemic in Europe as suggested recently.[24] A higher proportion of children with genotypes other than type 1 achieved a SVR to therapy, as has been reported by other paediatric studies.[24]

Additionally, in univariable logistic regression, children with genotype 1 were more likely to have consistently elevated ALT levels and consistently positive HCV RNA PCR results, although the associations did not reach statistical significance likely because of small numbers. This finding does however support those of Harris et al. who suggested that type 1 infections may be more aggressive than types 2 or 3[25] and those of a previous EPHN study which found that intrauterine vertical transmission was more likely to occur from mothers with genotype 1.[26]

As no differences in the genotype profile of vertically and parenterally infected children were found here, it is unlikely that any differences in biological or clinical markers of HCV infection between groups can be attributed to the possible differences in HCV progression by genotype.
In multivariable logistic regression, no association between consistently raised ALT z-scores and mode of acquisition was found, possibly because of a lack of power, although the odds ratio remained below one, indicating higher ALT z-scores in vertically infected children. ALT levels have been shown to peak in the first 2 years of life in vertically infected children[27–29] and to adjust for this peak and any other differences resulting from age at measurement, ALT z-scores were used. The finding of increased ALT z-scores in vertically infected children adjusted for age is similar to an Australian study in which significantly higher geometric mean ALT levels in 16 vertically vs 15 parenterally infected children in the first 5 years of life were found, again after accounting for the early peak in ALT levels.[20]

Significant positive associations were found between consistently high ALT z-scores and both consistent HCV RNA viraemia and ever having evidence of hepatomegaly. There was also a higher odds of having consistently positive HCV RNA PCRs in children ever having evidence of hepatomegaly but not significantly so. The associations between these three markers of HCV-related disease progression support previous studies indicating that they may define a group of children with evidence of chronic progressive HCV or who are at increased risk of rapid or more severe progression.[2] In this analysis, similar proportions of parenterally and vertically infected children had evidence of two or more of these markers of infection. Similarly, no difference was found in the proportion with two or more markers and age at infection, in either all children or just the parenterally infected group. This lack of association with mode of or age at acquisition may have been because of combining the markers of infection into this summary variable and also the small number (15 children) of parenterally and vertically infected children with evidence of two or more markers of infection.

The prevalence of comorbidities in parenterally infected children is high given the nature of their infection during receipt of medical treatment[30] and this may have been influential in terms of the child's ability to mount an initial or continued immune response to HCV infection. In contrast, vertically infected children, although acquiring infection during immune development may benefit from persistence of maternal antibodies.[20,31] These mechanisms require specific investigation and although evidence from this analysis does not support substantial differences between the vertically and the parenterally infected groups, until they can be further defined it is important that the potential differences between them are recognized in a clinical setting. This study also highlights the growing need for epidemiological data on parenterally infected children and the difficulties in analyzing such data. Recent estimates suggest that 40% of HCV infections worldwide are acquired via unsafe medical injections and a great number of these occur in children. It is therefore vital that knowledge of disease progression in parenterally infected children is accurate and that the differences between vertically and parenterally infected groups are clarified to inform more accurate and individualized clinical management.
Read More;
Abstract and Introduction
Materials and Methods
Results
Discussion
References

Pediatric Infectious Disease Journal: September 2011 - Volume 30 - Issue 9 - pp 801-804 doi: 10.1097/INF.0b013e3182196ab4 Brief Reports Impact of Human Immunodeficiency Virus Coinfection on the Progression of Mother-to-child Transmitted Hepatitis C Virus Infection Claret-Teruel, Gemma MD, PhD*; Noguera-Julian, Antoni MD, PhD*; Esteva, Cristina BSc†; Muñoz-Almagro, Carmen MD, PhD†; Sánchez, Emília MD, PhD‡; Jiménez, Rafael MD, PhD*; Fortuny, Clàudia MD, PhD* Abstract Data on mother-to-child transmitted human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection are scarce. A prospective observational study with a cohort of 70 HCV-infected children (13 of whom were HIV/HCV-coinfected; mean follow-up: 7.3 years) is presented. In our series, surrogate markers of disease progression (HCV viremia, maximum alanine aminotransferase values, and spontaneous HCV infection clearance) suggest that the evolution of liver disease in HIV/HCV-coinfected pediatric patients is more aggressive than it is in HCV-only infected children.



FDA Pediatric indication;Pegasys and Copegus

Pegasys and Copegus - pediatric indication for patients 5 -17 years of age

Title: FDA Hepatitis Update - Pegasys and Copegus - pediatric indication for patients 5 -17 years of age

On August 22, 2011, the FDA approved the combination of Pegasys and Copegus for the treatment of chronic hepatitis C virus (HCV) infection in pediatric patients 5 through 17 years of age with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha.. Pegasys/Copegus combination treatment for HCV in adults was approved in December, 2002, and that original approval included a postmarketing requirement to evaluate the drugs in pediatric patients.

Hoffmann-La Roche Inc submitted the results of Study NV17424 to support the use of Pegasys/Copegus in pediatric patients. Subjects participating in the study received Pegasys at a dose of BSA x 180 mcg/1.73 m2 once weekly plus Copegus at a dose of approximately 15 mg/kg/day in two divided doses. Study participants received 24 weeks of blinded treatment and were determined to be responding or not responding based on undetectable HCV RNA (< 50 IU/mL). Responders continued their assigned treatment to 48 weeks regardless of HCV genotype. Nonresponders were unblinded and either stopped treatment (if they were in the Pegasys/Copegus group) or rolled into a “compassionate” Pegasys/Copegus combination group to continue 48 weeks of treatment (if they were in the Pegasys/placebo group). Subjects were followed off-treatment for an additional 24 weeks after the completion of 48 weeks of treatment to assess the primary efficacy endpoint, the proportion of subjects achieving sustained virologic response (SVR), defined as undetectable HCV RNA at 24 weeks post-treatment. Any subject switching from randomized Pegasys/placebo to the compassionate combination Pegasys/Copegus was counted as a treatment failure.

The trial enrolled 114 previously untreated pediatric subjects 5 through 17 years of age (of whom 55% were less than 12 years old who were randomized to receive either combination treatment of Pegasys/Copegus or Pegasys/placebo. The initial randomized arms were balanced for demographic factors: 55 subjects received initial combination treatment of Pegasys/Copegus and 59 received Pegasys/placebo. In the overall study population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. As previously shown in adults, the combination of Pegasys/Copegus provided significantly better response rates as measured by SVR compared to treatment with Pegasys alone. The SVR rate for study subjects receiving Pegasys/Copegus was 53% (29/55) compared to 20% (12/59) in the group receiving Pegasys. Subjects with the more difficult to treat genotype 1 receiving Pegasys/Copegus demonstrated SVR of 47% (21/45) while the smaller subgroup with non-genotype 1 had higher SVR (80%, 8/10).

The safety profile of Pegasys with or without Copegus in pediatric subjects in the clinical trial was similar to that observed in adults receiving similar treatment. Seven subjects receiving combination Pegasys/Copegus treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Dose modifications because of adverse events and laboratory abnormalities occurred commonly in the pediatric trial, about 35% during the randomized treatment period in both arms. The most common reason for modification of Pegasys was neutropenia and the most common reason for dose reduction of Copegus was anemia. The most common non-serious treatment related adverse events reported among subjects receiving Pegasys/Copegus included influenza-like illness (91 %), headache (62%), gastrointestinal disorders (56%), injection site reactions (45%), irritability (31%), fatigue (27%), rash (20%), pruritis (15%), and insomnia and decreased appetite (13% each).

The most important pediatric-specific safety issue related to Pegasys/Copegus was growth delay. Pediatric subjects treated with Pegasys/Copegus combination therapy experienced a delay in gaining weight and height after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.

July

What's New -- Part 2: Viral Hepatitis in Children

What's New -- Part 2: Viral Hepatitis in Children
Hepatitis C, D, E, and G in Children
,
See Part One;  hepatitis A and B.
,
Ravi Jhaveri, MD
Authors and Disclosures Posted: 07/06/2011
,
What Do You Need to Know About Hepatitis in Kids?

A 28-year-old woman, new to the community, presents to the pediatric clinic of a rural community health center with her almost 1-week-old infant. She reports that she has "chronic" hepatitis C but denies taking any current medications. She is uncertain if the obstetric provider who she saw several months ago performed any testing, but she is certain she was not tested at the hospital where she delivered.
What will you do?
Why are the hepatitis viruses considered together? They have little in common from a virology standpoint other than that they infect the same organ. In general, the symptoms result from the body's immune response, not infection itself. The key differences are:

• Transmission route;
• Incubation period;
• Clinical manifestations; and
• Availability of a vaccine.

This activity is a continuation of Part 1 which discussed hepatitis A and B.

Continue Reading....


May-April 2011

Nature Reviews Gastroenterology and Hepatology
8, 247-248 (May 2011) | doi:10.1038/nrgastro.2011.61
Subject Categories: Hepatitis | Pediatric gastroenterology | Liver
Focus on: Viral Hepatitis

Viral hepatitis: Treating hepatitis C in children: an open horizon

Maria Guido & Flavia Bortolotti 
About the authors

Abstract
Most children with chronic hepatitis C have minimal liver disease before adulthood, but could be at risk of progression to cirrhosis and hepatocellular carcinoma because of persistent virus replication. The results of the first controlled trial with PEG-IFN-α2a plus ribavirin are a step towards an appropriate treatment for these children.

Chronic HCV infection is a global health problem. Children are a small, but far from negligible, portion of the infected population. In the USA, the NHANES III survey reported that anti-HCV antibodies were present in 0.2–0.4% of children 5–14 years old who were randomly surveyed,1 with similar rates seen in southern Europe.2 While the incidence of HCV infection has decreased considerably since the implementation of blood-screening strategies in blood banks, mother-to-infant transmission has become the primary mode of acquisition of new pediatric infections. Although only 5–6% of viremic mothers transmit the virus to their infants, the infection becomes chronic in >80% of these infants. Chronic hepatitis C has a mild course in most, but not all, infected children. The majority of children with chronic hepatitis C are asymptomatic; however, virus replication tends to persist into adulthood and cirrhosis might develop during the first 20 years of life, albeit rarely. In this setting, deciding whether or not to treat, who to treat, and what drugs to use has been a challenge. Indeed, the limited spread of HCV infection in childhood and the mild course of hepatitis C in its early stages has discouraged or delayed any decisions concerning its treatment. However, a recent study by Schwarz and colleagues confirms that children infected with HCV could benefit from early treatment.3

Following the successful experiences of combination therapy with PEG-IFN-α and ribavirin in adult patients with chronic hepatitis C, a few uncontrolled studies using this combination have been conducted in pediatric populations.4, 5 The largest study5 included 107 children, all treated with PEG-IFN-α2b (60 μg/m2 weekly) and ribavirin (15 mg/kg daily) for 48 weeks (patients with HCV genotypes 1 and 4, and those with HCV genotype 3 who had high viral loads) or 24 weeks (patients with HCV genotypes 2 and 3 with low viral loads). The study was conducted by experienced centers and yielded a sustained virological response (SVR) of 65% in all children, and 53% among the children infected with HCV genotype 1. Essentially on the basis of these results, at the end of 2008 the FDA approved the use of combination therapy with PEG-IFN-α2b and ribavirin in previously untreated children aged 3–18 years.6

The study by Schwarz et al.3 has the merit of being the only randomized, placebo-controlled trial on the safety and efficacy of PEG-IFN-α2a, with or without ribavirin, in children. A total of 114 children were enrolled in the study, 55 of whom (group 1) were randomly assigned to receive PEG-IFN-α2a (180 μg/1.73 m2 body surface area) and ribavirin (15 mg/kg orally in two daily doses), while 59 (group 2) received PEG-IFN-α2a and placebo for 24 or 48 weeks. The safety profile was similar in the two groups and comparable with that of the uncontrolled studies. An SVR was obtained in 29 children (53%) in group 1 and 12 children (21%) in group 2. Among the patients infected with HCV genotype 1, 47% in group 1 and 17% in group 2 achieved an SVR. These results confirm the findings of the large uncontrolled study;5 the PEG-IFN-α plus ribavirin combination is a step forward in the care of children with chronic hepatitis C. Such encouraging results prompt a reconsideration of the controversial issue of treating chronic hepatitis C in children.

The question of whether or not to treat children with hepatitis C is complex; the infection is usually mild and stable throughout infancy and childhood, but can progress during adulthood.6 Additional information on the natural history of chronic hepatitis C in children has emerged from a study published in 2008 that included 359 consecutive Italian children who were HCV RNA positive, had not received treatment and were followed up for a mean period of 10 years.7 Viremia cleared spontaneously in 8% of the children; these children were more likely to be infected with HCV genotype 3 than the other genotypes. In a few children who were infected with HCV genotype 1a, and had perinatal exposure and maternal drug abuse, persistent virus replication led to end-stage liver disease during childhood (1.8%). The vast majority (92%) of the children had persistent virus replication, with normal levels of alanine aminotransferase in one in three patients. Transient and mild symptoms were seen in 6% of the patients who were infected perinatally. Histology-based studies have demonstrated that liver inflammation and fibrosis in children infected with HCV are milder than in adults infected with HCV.8 Cirrhosis is rarely observed in children, but bridging fibrosis is frequent (4% of the patients enrolled by Schwarz et al.), which suggests that children with chronic hepatitis C will be at risk of progressive liver disease as they grow older.

The question of whether or not to treat children with hepatitis C is complex...

In a series of 112 pediatric patients infected with HCV who had no underlying disease or evidence of exposure to hepatotoxic factors, the duration of the infection correlated with the stage of fibrosis. In addition, all the children >15 years old had some level of fibrotic liver lesions, a finding that is compatible with a slow but dynamic process of disease progression.9 In this respect, chronic hepatitis C in children seems to be more insidious than is usually believed, and attempts to eradicate HCV as early as possible are justified to prevent disease progression. Several other reasons exist that support treatment of children infected with HCV, including: children's good tolerance of antiviral medication; few comorbidities in children, such as alcoholism; the positive cost:benefit ratio of treating children as they have a low body weight and total body surface area; and the benefits of eliminating the social stigma by eradicating the virus.

As the study by Schwarz et al. is placebo controlled, it removes any doubts concerning the efficacy of PEG-IFN-α combined with ribavirin, compared with PEG-IFN-α monotherapy, for the treatment of children and adolescents with chronic hepatitis C. In this study, female sex, nonmaternal HCV transmission, infection with HCV genotype other than genotype 1, low viral load, moderate or marked liver inflammation, and the absence of steatosis in the liver biopsy samples proved predictive of an SVR. In adults, virological response at 12 weeks (early virological response) is useful to predict SVR. Schwarz and colleagues emphasized that viremia cleared after completing the combination therapy in three of the 41 children infected with HCV genotype 1 who had not responded to treatment at 12 weeks. Consequently, they suggest that early virological response is not a reliable marker of SVR in children and, therefore, the lack of an early response is not enough to justify stopping their treatment. However, the small number of patients observed in this study prevents any firm conclusions from being drawn as yet. A genetic polymorphism near the IL28B gene on chromosome 19 is highly predictive of virus clearance with PEG-IFN-α plus ribavirin treatment in adults.10 Hopefully this finding will be replicated in children in the near future.

In conclusion, to date only a minority of children who have chronic hepatitis C have been given antiviral treatment, although their response rates to such treatment have been even better than in adults. The FDA's approval of the PEG-IFN-α2b plus ribavirin combination and the publication by Schwarz et al. of the only controlled study that analyzes PEG-IFN-α2a and ribavirin are important steps forward in the care of children with chronic hepatitis C, which will enable children to be treated outside clinical trials. Clearly detailed indications and guidelines are needed, preferably tailored to the characteristics of each subgroup of pediatric patients infected with HCV.

Competing interests statement The authors declare no competing interests.

References

1. Alter, M. J. et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N. Engl. J. Med. 341, 556–562 (1999).
   
   
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2. Bortolotti, F. et al. Epidemiological profile of 806 Italian children with hepatitis C virus infection over a 15-year period. J. Hepatol. 46, 783–790 (2007).
   
   
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3. Schwarz, K. B. et al. The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology 140, 450–458 (2011).
   
   
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4. Hu, J., Doucette, K., Hartling, L., Tjosvold, L. & Robinson, J. Treatment of hepatitis C in children: a systematic review. PLoS ONE 5, e11542 (2010).
   
   
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5. Wirth, S. et al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alpha-2b plus ribavirin. J. Hepatol. 52, 501–507 (2010).
   
   
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6. Ghany, M. G. et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49, 1335–1374 (2009).
   
   
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7. Bortolotti, F. et al. Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease. Gastroenterology 134, 1900–1907 (2008).
   
   
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8. Goodman, Z. D. et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial. Hepatology 47, 836–843 (2008).
   
   
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9. Guido, M. et al. Fibrosis in chronic hepatitis C acquired in infancy: is it only a matter of time? Am. J. Gastroenterol. 98, 660–663 (2003).
   
   
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10. Balagopal, A., Thomas, D. L. & Thio, C. L. IL28B and the control of hepatitis C virus infection. Gastroenterology 139, 1865–1876 (2010).
    
    
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uthor affiliations M. Guido & F. Bortolotti
Department of Medical Sciences and Special Therapies, Pathology Unit, University of Padova, Via Gabelli 61, 35128 Padova, Italy (M. Guido). Lionello Forin Hepatos Onlus Foundation, Via Martiri Giuliani e Dalmati 2/A, 35129 Padova, Italy (F. Bortolotti).
Correspondence to: M. Guido mguido@unipd.it
Published online 5 April 2011

Quality of Life for Children on Hepatitis C Treatment

By James Learned

SUMMARY
Children treated with pegylated interferon plus ribavirin or placebo experienced some worsening of physical symptoms after starting therapy, but most had no clinically significant changes in quality of life or emotional and cognitive functioning by the end of treatment.

Recent data indicate that children and adolescents with chronic hepatitis C virus (HCV) infection respond as well or better than adults to HCV treatment. Hepatitis C disease progression tends to be more benign in children compared with adults; however, almost 30% of children with chronic hepatitis C experience symptomatic progression, which can lead to cirrhosis and hepatocellular carcinoma later in their lives.

Many studies have examined quality of life (QOL) and psychological and cognitive effects of chronic HCV infection before and during treatment in adults, but little is known about these factors in children.

Recognizing that few studies address this issue -- and that somewhat contradictory findings have been published -- James Rodrigue from Beth Israel Deaconess Medical Center and colleagues set out to measure QOL, behavioral adaptation, depression, anxiety, and cognitive functioning in children undergoing interferon-based hepatitis C treatment, all of which are pertinent to childhood development.

The primary goals of the study included:

Achieving a better understanding of QOL and these other factors to help clinicians inform patients and their parents/guardians about possible side effects of treatment; Identifying the negative ramifications of chronic HCV infection and its treatment to facilitate the development and implementation of therapeutic and pharmacological interventions aimed at lessening unfavorable effects in children. As described in the May 2011 issue of Hepatology, researchers mined data from Peds-C, a prospective, multi-site, randomized study of 114 participants ages 5 to 18, all with chronic HCV infection; none of the participants had undergone hepatitis C treatment before.

Approximately half of the children (55) received once-weekly pegylated interferon alfa-2a (Pegasys) plus 15 mg/kg daily ribavirin, while the other half (59) received pegylated interferon plus placebo. Participants with undetectable HCV viral load at 24 weeks continued treatment for the full 48-week course. Participants in the pegylated interferon/ribavirin arm whose viral load was still detectable at week 24 were considered non-responders and treatment was discontinued. Children with detectable viral load at week 24 in the placebo arm were also considered non-responders and were offered open-label pegylated interferon plus ribavirin for 48 weeks.

Measures of QOL, behavioral/emotional functioning, and cognitive functioning were evaluated before starting treatment, at 24 and 48 weeks during treatment, 6 months after treatment, and at 2 subsequent annual visits. QOL and functioning were assessed based on various questionnaires and checklists, most of which were completed by a parent or guardian. Assessments included measures of the child's functional status, well-being, self-esteem, family impact, behavioral problems, emotional control, and mental health including anxiety and depression, among others.

The 114 participants had a median age of 10.7 years; 75% were white, 45% were female, and 75% had HCV genotype 1. All were treatment-naive. Other exclusion criteria included decompensated liver disease, serious depression, and a history of other severe illness. There were no significant differences between the 2 study arms in terms of sociodemographic or medical characteristics.

Results

After 6 months of treatment, average physical QOL scores declined significantly compared to baseline in both the pegylated interferon/ribavirin and pegylated interferon/placebo arms, although scores remained within the average range.

Overall, there was statistically significant worsening of bodily pain and general health at 24 weeks compared to baseline. However, there were no significant changes in behavioral/emotional or cognitive functioning at 24 weeks. Three children (5%) taking pegylated interferon/ribavirin -- but none of those taking pegylated interferon/placebo -- had significant increases in depression symptoms at 24 weeks.

 A majority of children who remained on treatment for the full 48 weeks in both the pegylated interferon/ribavirin and pegylated interferon/placebo arms experienced no clinically significant changes in QOL, behavior, depression, or cognitive functioning at the end of treatment or during follow-up.

Although 7 children (17%) who remained on treatment for 48 weeks experienced clinical decline in physical QOL, 5 of them returned to baseline QOL by the end of treatment or 6 months later.

Scores on all outcome measures did not differ significantly from baseline for any of the children who completed 48 weeks of treatment in either arm at the 1-year and 2-year follow-up evaluations.

Age, race, sex, route of HCV transmission, and baseline alanine aminotransferase (ALT) were not significantly associated with participants' QOL or other psychosocial outcomes at any time during the study.

The researchers described several limitations of their study. They presented data based primarily on parent or guardian input rather than from the children themselves, and acknowledged that "Such reports can be biased for many different reasons and, therefore, may not accurately capture the true functional status of the child."

Although the sample size was large compared to other published studies, the number of children who remained on their assigned treatment through the full 48 weeks was relatively small, and this may have limited the ability to detect small changes in QOL or functioning over time. Finally, the authors did not assess QOL and the other psychosocial outcomes until 24 weeks after treatment initiation. It is possible, they wrote, "that changes in these parameters occurred in the early stages of treatment and subsequently recovered by the time of our 24-week assessment."

Compared with adults, they suggested, children appear have less severe HCV disease, fewer medical and psychiatric problems, and more stable social support. These factors may account for the stability in quality of life and fewer problematic behavioral/emotional issues.

Based on their findings, the researchers concluded, "Previously, we reported that pretreatment scores for this HCV pediatric cohort were comparable to that of healthy children, and now we provide evidence that this remains largely unchanged after 48 weeks of peginterferon with ribavirin (or placebo) treatment and for 2 years after cessation of therapy."

"[F]or the few children who experienced clinically significant changes in QOL and behavioral/emotional functioning, almost all of them returned to healthy baseline levels by the end of treatment or by the 6-month follow-up assessment," they continued. "As the first randomized pediatric study to examine the QOL, psychological functioning, and cognitive impact of both peginterferon alone and with ribavirin, these findings have important clinical implications."

Investigator affiliations: Beth Israel Deaconess Medical Center, Boston, MA; Children's Hospital Medical Center, Cincinnati, OH; Children's Hospital of Philadelphia, Philadelphia, PA; Children's Hospital Boston, Boston, MA; George Washington University, Washington, DC; James Whitcomb Riley Hospital for Children, Indianapolis, IN; Children's Hospital and Regional Medical Center, Seattle, Washington; University of Colorado Denver School of Medicine, Children's Hospital, Aurora, CO; University of California, San Francisco, CA; Columbia University, New York, NY; Johns Hopkins University School of Medicine, Baltimore, MD; Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; University of Massachusetts Medical School, Worcester, MA; University of Florida College of Medicine and Shands Children's Hospital, Gainesville, FL.

5/24/11

Reference
James R. Rodrigue, William Balistreri, Barbara Haber, et al. Peginterferon With or Without Ribavirin Has Minimal Effect on Quality of Life, Behavioral/Emotional, and Cognitive Outcomes in Children. Hepatology 53(5): 1468-1475 (abstract). May 2011


Feb 2011
Children With Hepatitis C May Benefit From Ribavirin

Jan 2011

Treating Hepatitis C: Are Children the Same as Adults?

On The Blog; 2010 Articles