Treatment of Hepatitis C in children

Paloma Jara; Loreto Hierro

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

Abstract and Introduction

Abstract

Hepatitis C affects 4–10% of children born to infected mothers, and 80% of them develop chronic infection. Most patients with chronic hepatitis C virus infection are asymptomatic, with persistent or intermittent biochemical abnormalities. Severe liver disease may develop 10 years after onset of infection, with a less than 2% overall risk during the pediatric age. Available therapies have no contraindication in children if otherwise healthy. The US FDA and EMEA have recently approved combined pegylated-IFN-α2b plus ribavirin treatment for children, who should be over 3 years of age in order to avoid severe side effects. Experiences in pilot trials and international studies indicate a response rate of 50% in genotype 1 patients, and more than 90% in genotype 2 or 3 patients, indicating resolution of chronic disease.

Introduction

The possibility of curing chronic hepatitis C virus (HCV) infection by means of PEG-IFN plus ribavirin – the currently recommended treatment – has raised controversy about the convenience of treating pediatric patients. As children with chronic HCV infection are usually asymptomatic and rarely develop severe liver damage, the possibility of eliciting adverse effects from current therapies must be appropriately balanced against the benefits. Characteristics of HCV infection in children and the results of treatment are reviewed here in order to substantiate decisions.

The discovery of HCV and the use of anti-HCV levels as a marker of exposure was available in the early 1990s to exclude infected blood and organ donors. Before this, most HCV infections were acquired by transfusions or inadequately sterilized needles or instruments. Pediatric populations heavily affected in the past due to repeated administration of blood derivatives for hemoglobinopathies, hemophilia or cancer treatment are now young adults, and therefore beyond the scope of this revision. In certain areas of the world, post-transfusional hepatitis C remains a hazard. Cumulative information on superimposed HCV infection to some underlying diseases of children indicates similar chronicization rates, deleterious effects of iron overload added to viral-induced liver damage and evidence of difficult-to-treat patients because of conditions that affect the tolerability of drugs, such as anemia or renal insufficiency.

The effectiveness of excluding parenteral routes of HCV is demonstrated in young populations of industrialized countries.^[1] Perinatal mother-to-child transmission accounts for 95% of all cases of hepatitis C in children born after 1990. In addition, over the years there has been a reduction in the number of pediatric cases of vertical transmission because the anti-HCV-positive rate has decreased in younger women as a result of lesser transfusional transmission of the disease, and due to changes in illicit drug abuse with a shift towards nonintravenous forms of administration.^[2]

In the current setting, most affected children are otherwise healthy. The applicability of treatment is the rule. Combined treatment offers a 50–90% chance (according to HCV genotype) of clearing HCV infection, thus avoiding the progression of liver disease. This review will focus on the benefits of current therapy, mostly evident in the long term, and also on drug toxicity.

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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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