Treatment of Hepatitis C in children

Paloma Jara; Loreto Hierro

Expert Rev Gastroenterol Hepatol. 2010;4(1):51-61.

Course of HCV Infection in Children

In order to know the characteristics of HCV infection in children from the onset, many studies aimed at the surveillance of children born to HCV-positive mothers. HCV screening is not mandatory in pregnant women, as no intervention can be carried out to prevent transmission. In large hospital series, the rate of anti-HCV-positive women is approximately 0.6%, of whom 60% are viremic. The reduced number of infected children (4–10% of those born from viremic mothers) requires collaborative studies, with an extended time for recruitment of children from several centers.

No symptoms are observed at the beginning of hepatitis C. In a series of 70 children with vertical transmission, the majority (93%) developed aminotransferase elevations 1.2- to 21-times the normal values in the first year of life, with maximum values occurring either in the first or second semester.^[16] None developed hepatitis with jaundice. Overall, 62 out of 70 children could be followed up to 24 months of age or more. The cumulative probability of HCV RNA persistence was 90% at 2 years, 81% by the end of the third year of life and 81% at the fifth year. A sustained alanine aminotransferase (ALT) normalization with clearance of HCV RNA was observed in 12 out of 62 (19%) patients starting from the second year of life or the beginning of the third year. All those cured children remained anti-HCV positive.^[16]

According to the European Pediatric Hepatitis Network (EPHN) the estimated proportion of children with clearance of viremia, out of 155 children with HCV infection observed from birth, was 17% by 2 years of age, 24% by 3 years and 30% by 5 years.^[17] No patient cleared infection beyond the fifth year. The tendency towards chronicity showed no gender-based difference. In contrast to the aforementioned study, many of the children with a resolved infection evolved to a negative anti-HCV status in this study.

A retrospective Canadian study on 39 children with neonatal infection found a 25% probability of clearing infection by 7 years of age. Clearance occurred in 30% of nontransfusional and 16% transfusion-associated hepatitis C. No further clearance was observed beyond 7 years.^[18]

Genotype influences clearance rates. Children with genotype 3 infection had the highest ALT levels and the highest rate of spontaneous viremia clearance.^[16] In a series of 119 Italian cases diagnosed within the first 3 years of life, clearance rates were 5, 2.5, 7, 32 and 6% for genotypes 1a, 1b, 2, 3 and 4, respectively.^[19]

Overall, prospective studies show that 80% of children develop chronic infection, the diagnosis being established in those who remain HCV RNA-positive at 3 years of age. Spontaneous clearance after that time is unlikely.

The chronicity rate of HCV in children infected at birth does not differ from that of adults or children infected at older ages. Nearly 70% of children with inherited bleeding disorders or leukemia develop chronic infections.^[20,21] Serologic cross-sectional surveys show that 75–85% of anti-HCV-positive adults display positive HCV RNA. However, some series of children infected during cardiac surgery and two cohorts of young women infected by contaminated immune globulin had a chronic infection rate of 55%.^[22–24]

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Abstract and Introduction
Origin of HCV Infection in Children: Mother-to-child Transmission
Course of HCV Infection in Children
Liver Damage in Pediatric Chronic HCV Infection
Severe Liver Disease in Children
Outcomes in Adult Age
Treatment
Conclusion
Expert Commentary
Five-year View
References
Sidebar

Table 1. Liver damage in children with chronic hepatitis C.
Study	Country	Children (n)	Age at biopsy (years)	Comorbid conditions (%)	Scoring system	Grade, activity (0–18)	Stage Ishak 0–6, Knodell 0–4	Cirrhosis	Factors associated with fibrosis progression	Ref.
Iorio et al. (2005)	Italy	64	8.2 (2–14)	None	Ishak	Median: 4.4 Range: 1–8	Median: 1.6	0	Age or duration not related to fibrosis	^[31]
Mohan et al. (2007)	USA	42	15 ± 1.8 (cohort) 8.8 ± 5 (referral)	26	Knodell	71% mild (0–8), 5% severe (>13)	88% mild (0–1)	0 initial, 14% in follow up	Age of infection shows positive correlation with fibrosis (in referral group)	^[32]
Harris et al. (2007)	UK	98	14 ± 3.5	54	Ishak	Median: 3 Range: 1–7	Median: 1 Range: 0–6	3%	Comorbid conditions, OR: 7.1 Duration of infection in children with comorbidities Female, OR: 0.31	^[33]
Jara et al. (2003)	Spain–Italy–Belgium	92	1–17	None	Ishak	Mean ± SD: 3.9 ± 2, 76% mild (0–6)	1.6 ± 1.3	1%	Age > 15 years	^[26]
Goodman et al. (2008)	PEDS-C USA	121	Mean 9.8	No	Knodell	Mean: 5.1 59% mild, 3% severe	80% some fibrosis	2%	Fibrosis scores correlated with inflammation, but not with age Overweight	^[34]

OR: Odds ratio; PEDS-C: PEG-interferon with or without ribavirin in children with chronic hepatitis C trial; SD: Standard deviation.

Table 2. Efficacy of combined treatment in children.
Study	Treatment schedule	Children (n)	SVR overall (%)	SVR genotype 1	SVR genotype 2&3	SVR parenteral	SVR vertical	SVR		Ref.
Study	Treatment schedule	Children (n)	SVR overall (%)	SVR genotype 1	SVR genotype 2&3	SVR parenteral	SVR vertical	Age <12 years	Age >12 years	Ref.
Wirth et al. (2002)	IFN-α-2b 3–5 MU/m² three-times weekly + RBV 15 mg/kg/day	41	61	18/34 (52.9%)	7/7 (100%)	9/16 (56%)	14/21 (66%)			^[51]
Gonzalez-Peralta et al. (2005)	IFN-α-2b 3 MU/m² three-times weekly + RBV 15 mg/kg/day	118	46	33/92 (36%)	21/25 (84%)			43/75 (57%)	11/43 (26%)	^[52]
Wirth et al. (2005)	PEG- IFN-α-2b 1.5 µg/kg/week + RBV 15 mg/kg/day	61	59	22/46 (47.8%)	13/13 (100%)	19/27 (70.4%)	12/25 (48%)			^[62]
Jara et al. (2008)	IFN-α-2b 1 µg/kg/week + RBV 15 mg/kg/day	30	50	12/26 (46%)	3/3 (100%)	7/9 (78%)	8/21 (38%)	9/20 (45%)	6/10 (60%)	^[61]
P02538 study (2008)	IFN-α-2b 60 µg/kg/week + RBV 15 mg/kg/day	107	64	53%	93%					^[58]
PEDS-C trial (2008)	IFN-α-2a 180 µg/1.73 m²/week + RBV 15 mg/kg/day	55	53	47%	Non-1: 80%					^[60]

PEDS-C: PEG-interferon with or without ribavirin in children with chronic hepatitis C trial; RBV: Ribavirin; SVR: Sustained virologic response.

Table 3. Adverse events of combined treatment in children.
Study	Treatment schedule	Children (n)	Discontinuation due to AE	Reduced IFN due to AE (%)	Number of severe AE	Severe AE (n)	Permanent AE (n)	Ref.
Wirth et al. (2002)	IFN-α-2b 3–5 MU/m² three-times weekly + RBV 15 mg/kg/day	41	1 (2.4%)	0	4	Anemia: 1 Hypothyroidism: 3	0	^[51]
Gonzalez-Peralta et al. (2005)	IFN-α-2b 3 MU/m² three-times weekly + RBV 15 mg/kg/day	118	8 (7%)	31	6	Suicide attempt: 1 Suicide ideation: 1 Depression: 1 Hypothyroidism: 2 Hypothyroidism + diabetes: 1	1 hypothyroidism + diabetes	^[52]
Wirth et al. (2005)	PEG- IFN-α-2b 1.5 µg/kg/week + RBV 15 mg/kg/day	61	1 (1.6%)	5	7	Injection site reaction: 1 Hypothyroidism: 5 Diabetes: 1	1 diabetes	^[62]
Jara et al. (2008)	PEG-IFN-α-2b 1 µg/kg/week + RBV 15 mg/kg/day	30	3 (10%)	23	3	High fever: 1 Hyperthyroidism: 2	0	^[61]

AE: Adverse event; RBV: Ribavirin.

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