Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality worldwide. It is a leading cause of cirrhosis and a risk factor for hepatocellular carcinoma. In the UK, hospital admissions for HCV-related liver disease continue to increase; 10–15% of liver transplants in adults are due to HCV infection.[1] Deaths each year attributable to HCV infection are also continuing to rise.

In 2003, the prevalence of HCV infection in adults aged 15–59 years in the UK was predicted to be 0.53%, with the majority of infected adults having a history of current or prior intravenous drug use.[1] Many infected individuals remain unaware of their HCV status. The Departments of Health across the UK have launched an awareness campaign to encourage those with risk factors to be tested, so that they may be referred for appropriate and timely management.[2]

The importance of establishing a diagnosis of HCV infection in children is increasing. Although often asymptomatic, the risk of developing significant liver disease increases with time. Of crucial significance is the recognition that treatment strategies for HCV infection may be more successful and better tolerated during childhood than in adults. Furthermore, HCV eradication in children will reduce the infection risk they pose to others. Diagnosis and management of HCV infection in children is estimated to pose a significant economic burden over the next decade.[3] However, treatment strategies have been shown to be more effective in terms of quality-adjusted life-years saved and less expensive compared with no treatment.[4]

This article provides guidance and practical advice on the diagnosis and current management of hepatitis C in children and is aimed at all healthcare professionals involved in counselling, testing, and treating families. The treatment strategies reflect those currently being used for children in the UK.

1. Establishing the Diagnosis

1.1 Who to Test

Since blood product screening for HCV infection was introduced in 1990, most children who acquire HCV do so by vertical transmission from an infected mother.

In the UK, the estimated seroprevalence of HCV in pregnant women is 0.16%.[5] Transmission to offspring occurs in approximately 5%, and the risk of transmission is increased by the level of HCV viremia and HIV co-infection in the mother. It is estimated that 1150 pregnancies annually in the UK would involve a woman infected with HCV, leading to approximately 70 infected infants being born each year.[5] However, in most infected women, risk factors for HCV are not identified and the diagnosis not established.[6] Routine antenatal testing for HCV is not currently recommended and thus the risk to their offspring may not be identified.

Transmission of HCV through infected blood led to a large number of children with, for example, thalassemia, leukemia, or hemophilia acquiring HCV prior to 1990. Transmission through infected blood products, however, remains a risk in countries where stringent recommendations for screening blood products are not reliably adhered to. Another risk factor for the acquisition of HCV is organ transplantation. Horizontal transmission from family members is uncommon.

Most children with HCV infection are asymptomatic, and may remain so for decades. Delaying diagnosis until the onset of symptomatic chronic liver disease would result in medical treatment opportunities being missed, and liver transplantation may become the only option. Early diagnosis is therefore made by encouraging those at risk to be tested, and also by considering HCV as a potential cause of any minor liver dysfunction, irrespective of risk factors.

Diagnostic testing for HCV should therefore be considered in the following circumstances:

  • infants born to HCV-infected mothers;

  • infants born to mothers with risk factors for HCV;

  • children who have been exposed to blood products/hospitalization where adequate HCV prevention measures are not routine; and

  • children with unexplained liver dysfunction.

1.2 How to Test

Two techniques are in common use for detecting HCV infection: HCV RNA detection by polymerase chain reaction (PCR) and HCV antibody (anti-HCV) testing by enzyme immunoassay (EIA). Anti-HCV detection provides evidence of HCV infection but does not differentiate ongoing viremia from resolved infection. Even after clearance of HCV RNA, anti-HCV may persist for years. A further pitfall of anti-HCV testing in infants is the inability to distinguish passively transferred maternal antibodies from that produced by an infant following infection. Anti-HCV detected prior to 18 months of age may still be maternal in origin.

HCV RNA detection signifies ongoing viremia, and is thus the most useful technique in most clinical settings. There may be a window phase after initial infection where the level of viremia remains below the detectable threshold and, thus, a false negative result may occur. It is therefore recommended that infants born to infected mothers are tested at or after 3 months of age in order to overcome this pitfall. A positive HCV RNA test in any situation should be confirmed by repeat testing. Individuals with persistence of HCV RNA beyond 6-months’ duration are deemed to have chronic (or persistent) infection. Inflammation of the liver from persistent HCV infection is termed chronic hepatitis. These terms are not synonymous, as chronic infection may occur without giving rise to liver inflammation.

Although anti-HCV and HCV RNA testing can determine the presence of HCV infection, they do not assess its clinical significance. Elevation of hepatic aminotransferase enzyme levels provides a surrogate marker of inflammatory activity, and liver biopsy yields more reliable evidence of the degree of inflammation and fibrosis.

Hepatitis C genotype testing should be performed in all children who are HCV RNA positive. There is considerable variation in response to treatment depending on genotype (see section 2) and, thus, identification of the genotype informs the decision to treat or defer treatment.

2. Management Strategies

The evolution and improved efficacy and tolerability of treatment strategies for HCV infection have had a significant impact on the management of both adults and children. The emphasis has now changed towards promoting awareness, and early diagnosis and treatment.

The potential role of interferon alfa (IFNα) in the treatment of HCV infection was first reported in 1986, when ten adults with chronic ‘non-A, non-B’ hepatitis showed improved aminotransaminase levels and improved histology.[7] IFNα is an endogenously produced protein with antiviral, antiproliferative, and immunomodulatory activity. Together with other endogenous interferons (β, ω, λ) it has an important role in the host immune response. The antiviral activity of IFNα is mediated by induction of an array of IFN-stimulated genes, which are involved in both antiviral and other cellular processes. Exogenous recombinant IFNα works through the same cell receptor activation, but higher concentrations can be achieved.[8] In addition to antiviral effects, IFNα has a variety of immune modulatory effects, including the promotion of T-cell proliferation, stimulation of natural killer cell activity and up-regulation of major histocompatibility complex (MHC) antigen expression.

Since then, HCV treatment strategies for adults have evolved from single-agent therapy with IFNα to combination therapy with IFNα and ribavirin. Pegylated IFNα proved to be superior to non-pegylated IFNα as monotherapy, and now forms the basis of the current National Institute of Clinical Excellence (NICE) recommendations for treatment of HCV infection,[9] in combination with ribavirin. The covalent attachment of a polyethylene glycol moiety to recombinant IFNα (‘pegylation’) enhances its half life and removes its immunogenicity. Polyethylene glycol-IFNα has similar adverse effects to non-pegylated IFNα, but has the advantage of once weekly, rather than thrice weekly, injections. Two different pegylated IFNα products are available: pegylated IFNα-2a (Roche Laboratories, Nutley, NJ, USA) and pegylated IFNα-2b (Schering-Plough, Kenilworth, NJ, USA). They differ in the structure of the polyethylene glycol moiety, which alters their size and volume of distribution, and pharmacokinetic profile. Each therefore has its own specific dosage schedule. There appears to be no difference in efficacy.[10]

Ribavirin has broad antiviral activity. Although effective against viruses such as respiratory syncytial virus, it is not effective as a single agent against HCV infection. It does, however, have a synergistic effect with IFNα, and has become established in combination therapy for this indication. It may have a direct effect on HCV RNA replication but it is also hypothesized to lead to ‘lethal mutagenesis’: by increasing the mutation frequency of HCV, ribavirin may impede the ability of HCV to replicate, infect new cells and escape the immune response. Ribavirin also appears to have immunomodulatory effects, and may also augment intracellular effects of interferon.[8,11]

The efficacy of treatment regimens may be measured in terms of biochemical and histologic improvement, but the most widespread and objective endpoint is that of sustained viral response (SVR), defined by HCV RNA remaining undetectable 24 weeks after the end of treatment. Both recombinant IFNα and its pegylated equivalent has two commercially available preparations: IFNα-2a and IFNα-2b. They appear to have similar efficacy in terms of SVR, and treatment recommendations for adults do not differ between the products. Efficacy results from four randomized, controlled trials in which intervention regimens in adults were compared are shown in table I. The superior efficacy of combination therapy with pegylated IFNα and ribavirin compared with earlier regimens is demonstrated.

Table I
figure Tab1

Efficacy of treatment for hepatitis C virus infection in adults

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The genotype of HCV has an important influence on treatment efficacy, with patients with HCV genotype 1 having inferior response rates to patients with other HCV genotypes (table II).

Table II
figure Tab2

Effect of hepatitis C virus genotype on response to treatment

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However, benefits of treatment are not restricted to biochemical, histologic or virologic response: quality of life, risk of hepatocellular carcinoma, and mortality risk may be favorably affected by treatment, even in the absence of sustained viral response.[16,17]

With increased knowledge of factors affecting response, recommendations for treatment duration now vary to reflect the HCV genotype, initial level of viremia, and initial response to treatment. In 2006, a significant recommendation from NICE was that treatment should be extended to adults with mild chronic hepatitis C, and not restricted to those who had progressed to biopsy-proven moderate to severe hepatitis C.[10] Although children under 18 years of age are not within the scope of these recommendations, they are otherwise likely to fulfill the criteria in the NICE recommendations and, thus, merit consideration for treatment.

3. Studies of Hepatitis C Virus (HCV) Infection Therapy in Children

Studies of treatment for HCV infection in children have used the same drugs and measures of efficacy as in adults (see section 2), but have been limited to relatively small numbers of children.

A meta-analysis of 19 trials of IFNα for children with HCV infection examined the effect of treatment in 366 children compared with 105 untreated controls.[18] Response to treatment occurred in a mean of 54% (range 0–91%) of patients, with a sustained response in 36% (0–73%). HCV genotype 1 adversely affected the likelihood of response, with a sustained response in 27% of children compared with 70% in those with other genotypes. The spontaneous clearance rate in untreated children was 5%. Treatment regimens varied, with duration of therapy ranging from 6 to 18 months. Most studies used a dosage of 3 MU/m2 via subcutaneous injection 3 times weekly, although higher and lower doses were also used. A small study of pegylated IFNα as monotherapy for 48 weeks in 14 children achieved a SVR in 43% of children with HCV genotype 1.[19]

As in adults, studies of combination therapy with IFNα or pegylated IFNα and ribavirin in children support its efficacy in achieving sustained HCV RNA clearance (SVR) and improved likelihood of response compared with IFNα alone (table III).[18–22] A pilot study of pegylated IFNα and ribavirin suggests similar efficacy:[23] a multicenter European study of this combination therapy is in progress, and in the US a randomized, double-blind, placebo-controlled trial of pegylated IFNα monotherapy versus combination therapy with ribavirin is being performed.[24]

Table III
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Efficacy of treatment for hepatitis C virus infection in children

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4. Adverse Effects

IFNα (including pegylated IFNα) is better tolerated in children than in adults, although some adverse effects are common. These include flu-like symptoms, fatigue, and neutropenia. Alopecia, pruritus, rash, and gastrointestinal disturbance (diarrhea, anorexia, nausea, abdominal pain) leading to weight loss may also occur. Mood disturbance including irritability, insomnia, and somnolence can occur: more severe adverse effects including depression and suicidal ideation are more common in those with a pre-existing mood disturbance or those receiving treatment during adolescence. Abnormalities of thyroid function and reversible hypothyroidism also occur. In a study of IFNα and ribavirin in children[21] 6 of 28 (21%) treated for >6 months, developed thyroid autoantibodies. Of these, three also developed raised thyroid stimulating hormone (TSH) levels and required supplementary thyroid hormone during therapy. All adverse effects disappeared after the end of treatment.

The most common adverse effect of ribavirin is a reversible hemolytic anemia, which occurs due to accumulation of phosphorylated ribavirin in erythrocytes which shortens their life span. A fall in hemoglobin level between 2 and 3 g/dL within 4 weeks of starting combination therapy is common, but significant anemia occurs in <10% of adults.[25] Ribavirin is also known to be teratogenic.

Although these adverse effects may be less prominent in young children, who tolerate the combination therapy well, contraindications (see table IV) must be carefully considered prior to starting treatment.

Table IV
figure Tab4

Pretreatment assessment of children with hepatitis C virus (HCV) infection

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Reduction or temporary discontinuation of interferon and/or ribavirin may ameliorate adverse effects. However, this may also jeopardize the success of treatment. Adherence to treatment in adults with HCV genotype 1 has been shown to have a significant impact on the likelihood of response, with those adhering to >80% of treatment having a superior response.[26]

5. Recommendations for Treatment in Children

Treatment should be considered in all children >3 years of age.[27] Timing of treatment should take into account both patient age and stage of schooling, avoiding stressful times, together with HCV genotype. If treatment is deferred, monitoring of the disease should continue, in order to identify those with histologic progression that would further influence the decision to treat.

Clinical guidelines on the management of hepatitis C in adults, compiled on behalf of the Royal College of Physicians of London and the British Society of Gastroenterology,[28] suggest that “Patients infected with HCV should be referred to a clinician with a particular interest in the infection. Patients must have access to adequate counseling from a healthcarer with a knowledge and experience of chronic HCV infection. All patients must have access to the appropriate diagnostic and therapeutic options…”. Furthermore, NICE recommendations state that “Treatment for chronic hepatitis C should be provided by physicians who are expert and experienced in the diagnosis and management of viral hepatitis, and a clinical nurse specialist for hepatitis with access to supportive services including an accredited virology laboratory, a liver pathologist and a radiology department, consistent with Department of Health (2002) Hepatitis C Strategy for England”.[9] Although such formal guidelines have not been compiled for children, it is our opinion that the case for delivering care under the supervision of specialist pediatric liver services is even more important for children; such pediatric services are few in number and expertise is therefore limited.

At present, there is no evidence to support a different dose (based on surface area and bodyweight) or duration of treatment than that recommended for adults. Pretreatment assessment of children with HCV infection, and recommendations for monitoring of treatment and adverse effects and dose modification are presented in tables IV, V, and VI respectively.

Table V
figure Tab5

Treatment regimen for children with hepatitis C virus (HCV) infection and monitoring during treatment

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Table VI
figure Tab6

Recommended dose modifications during treatment

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6. Management of HCV in Children Requiring Special Consideration

A proportion of children with HCV infection have significant co-morbidity, either due to co-infection with other viruses (particularly HIV), or a disorder that increased their susceptibility to HCV due to exposure to infected blood products. Although both IFNα and ribavirin may be contraindicated, the risks and benefits must be considered before denying treatment.

6.1 Anemia

Anemia in patients with HCV infection is more common in those with HIV co-infection, renal insufficiency, thalassemia, or cirrhosis.

Both IFNα, by bone marrow suppression, and ribavirin-induced hemolysis may contribute to anemia during treatment. Individuals with pre-existing anemia may therefore have a fall in hemoglobin level with treatment which is clinically significant, contributing to fatigue and breathlessness, and reducing quality of life. Strategies that have been tried to minimize anemia include reduced ribavirin dose and administration of erythropoietin. Reduced ribavirin dose to <60% of the total cumulative dose, however, has been shown to reduce the likelihood of SVR.[29,30]

Erythropoietin and the long-acting darbepoetin alfa have been demonstrated to increase hemoglobin levels, thereby increasing the likelihood of maintaining the ribavirin dose, and also improving quality of life during treatment. However, the effects of erythropoietin-containing regimens on SVR are uncertain, and these regimens contribute to treatment burden and cost.[25]

6.2 Thalassemia

Treatment of individuals with thalassemia and HCV infection requires special consideration. It is more likely that these patients have significant hepatic fibrosis, due to the combination of iron overload and HCV infection, but this does not appear to compromise treatment efficacy. However, due to anemia, ribavirin may be contraindicated, and a fall in hemoglobin level during treatment may add to the transfusion requirement and potential for iron overload.

There is evidence to support IFNα monotherapy as first-line treatment, with encouraging response rates.[31] However, in a small randomized trial of 20 patients with thalassemia and HCV infection, SVR in those receiving combination therapy with pegylated IFNα-2a and ribavirin was 62.5% compared with 30% (p = 0.19) with monotherapy.[32] Transfusion requirements increased by 34% in those receiving ribavirin but did not necessitate increased chelation therapy.

6.3 Liver Transplant

HCV infection in adults is a leading indication for liver transplantation. Reinfection post-liver transplantation is universal and 25–33% of those with recurrent HCV develop advanced disease within 5 years.[33–35]

Unlike in adults, it is rare for children to require liver transplantation for HCV infection. However, the experience of 67 children undergoing orthotopic liver transplantation for HCV infection between 1988 and 2005 has been reported. Retransplantation was indicated in 31%, the majority being for HCV recurrence after a median of 290 days, an outcome similar to that described in adults.[36]

Post-liver transplantation treatment strategies are suboptimal: treatment is less well tolerated and less effective. Immunosuppression reduces the effectiveness of combination therapy and may stimulate acute and chronic rejection in 10–25% of those receiving HCV treatment.[37] Furthermore, immunosuppression with calcineurin inhibitors such as tacrolimus and ciclosporin may potentiate ribavirin-induced anemia.

Treatment strategies have included pre-emptive combination therapy with IFNα and ribavirin, starting early after liver transplantation. This has been associated with a 50% incidence of adverse events, and SVR of 10–20%. Treating after HCV disease is re-established is associated with improved efficacy results (SVR of 25–40%). However, efficacy remains lower in this population than in those without a liver transplant.[38,39]

7. Future Treatment Strategies

Further refinements of IFNα and ribavirin combination therapy are underway. Ribavirin analogs, such as the prodrug viramidine, are undergoing clinical studies. Viramidine is more liver specific and may reduce the risk of hemolytic anemia.[40] A recombinant protein of IFNα-2b genetically fused with albumin, with the potential of a monthly rather than weekly injection regimen, is also being evaluated.[41]

New drugs in development continue to target either inhibition of viral replication, such as protease and polymerase inhibitors, or modulation of host immune response, including Toll-like receptor agonists. Both strategies are undergoing clinical evaluation.[42–44] Toll-like receptors are expressed by a range of immune cells, and after stimulation by a micro-organism they initiate an acute inflammatory response through antimicrobial gene and cytokine induction.

Gene therapy strategies undergoing trials in animal models include the transfer of the IFNα gene into a mouse model, and also the integration of antisense DNA/RNA molecules into a host genome to render hepatocytes resistant to viral infection.[45]

Other molecular strategies involve RNA interference: synthetic or expressed RNA forms target and degrade genomic RNA or RNA replication intermediates and transcripts. RNA interference strategies are being evaluated in cultured cells and mice.[46]

Phase I clinical trials of a human monoclonal antibody against hepatitis C virus are in progress: safety and antiviral efficacy have been reported.[47]

Recent developments which have led to optimism in the development of a vaccine for HCV include an HCV culture model that is infectious for chimpanzees. Vaccine efficacy data in chimpanzees indicate that it appears feasible to impede progression to chronic infection.[48–50] Furthermore, characterization of the natural immune response resulting in viral clearance has informed vaccine development. Vaccine candidates are undergoing phase I and II treatment trials.[51]

8. Conclusions

HCV infection is prevalent worldwide. The introduction of screening of blood products has reduced parenteral transmission, but intravenous drug use continues to promote the transmission of virus between individuals. Children were previously at risk through infected blood products, but now their major route of acquisition is perinatally from an infected mother. Molecular diagnostic strategies include HCV RNA detection and HCV genotyping, which will identify those infected and inform treatment decisions. Treatment strategies have evolved, from monotherapy with IFNα to combination therapy with pegylated IFNα and ribavirin, with improving tolerability and response rates. Children with established infection but early disease should be considered for treatment.