Chronic Hepatitis C in Children
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.
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