Treatment of Hepatitis C in children

Paloma Jara; Loreto Hierro

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

Liver Damage in Pediatric Chronic HCV Infection

Data are derived from vertically infected children identified in prospective studies and series of children who were found to have HCV chronic infection at varying times of life, when screened because of risk exposures or asymptomatic aminotransferase elevation. Provided the children are otherwise healthy and not affected by chronic illnesses, the characteristics of chronic HCV infection are not related to the mode of infection acquisition (parenteral or vertical route).^[25]

Chronic HCV infection is usually an asymptomatic disease. Nearly 15% of children present nonspecific, mild and transient symptoms at the time of initial diagnosis, probably related to intercurrent illness that leads to HCV detection. Hepatomegaly is noted in 10% of infants. HCV-associated cryoglobulinemia, vasculitis and porphyria cutanea tarda are not reported.

During chronic infection, different patterns of biochemical abnormalities are observed. In two large series of 194 and 332 children, respectively, ALT levels were persistently abnormal in 42–45% of patients, normal or normalized in 8–23% and intermittently elevated in 35–41%.^[26,27]

The predominant genotypes in European and American children are 1a and 1b (70%), although in recent years, and considering children with vertical transmission, the proportion of genotype 1 infections has decreased to 54%, with a rise in genotypes 3 (23%) and 4 (7%).^[19] The viral load does not appear to be correlated to ALT levels or the histologic lesions.^[28]

A biopsy is needed for accurate assessment of lesions produced by chronic hepatitis. Although not performed in every affected child, it usually reveals mild lesions. Noninvasive biochemical tests (Fibro-Test and Acti-Test) are being evaluated in children with hepatitis C for their correlation with histology.

In a study of Italian and Spanish children, the histologic activity index (HAI) was found to be low in most patients, with a mean value of 3.6 (range 0–11). The final diagnoses were normal liver histology or with minimal and nonspecific lesions in 17.5% of the cases, chronic hepatitis with a low activity in 60% and high activity in 21%. Those patients with a definitive diagnosis of highly active chronic hepatitis were significantly older on average (12 years) than children with low-activity chronic hepatitis or minimal liver lesions (8 years). Fibrosis was absent in 27.5% of cases, mild in 55% and moderate in 16.2%. Only 1.3% (one of the 80 children) had cirrhosis. A significant relationship was detected between fibrosis scores and duration of disease, portal inflammation and interface hepatitis.^[29]

In a later report with additional children (total of 112 cases) fibrosis was assessed by the METAVIR scale.^[30] Age of patients at biopsy and duration of infection strongly correlated with fibrosis stage. A strong difference was observed between patients whose infection lasted less and more than 10 years. The mean rate of 'estimated' fibrosis progression in a linear progression model was 0.227 ± 0.372 METAVIR units per year, with a median of 0.142. Theoretically, cirrhosis could develop after a mean time of 28 years. However, the rate of 'observed' fibrosis progression per year in the 13 subjects who underwent paired biopsies was variable among them (seven had increased and six unchanged scores), averaging 0.112 ± 0.14. The progression of fibrosis seems to be a function of the duration of the infection, when no other risk factors for liver damage are present.

Similar histologic findings have been reported in several series, some of which included patients affected by other superimposed conditions to HCV (Table 1).^[26,31–34]

A recent report on 121 children without decompensated disease and recruited in several American centers for a therapeutic trial^[34] has shown that children with normal ALT were as likely to have significant inflammation as those with elevated ALT levels. Five patients (4.2%) had bridging fibrosis and two (1.7%) had cirrhosis. There was a highly significant correlation of inflammation with fibrosis. In the subset of 94 children with perinatal transmission, there was a weak correlation of estimated duration of disease with inflammation that approached statistical significance. The two children with cirrhosis were both 14 years old, whereas the five with bridging fibrosis were 11–16 years old. The lack of correlation of age or duration of infection with fibrosis might have been due to the small number of patients with advanced fibrosis.

Other authors found the severity of liver disease did not seem to depend on the duration of infection.^[31]

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Cite this: Treatment of Hepatitis C in children - Medscape - Feb 01, 2010.

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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