Paloma Jara; Loreto Hierro
Expert Rev Gastroenterol Hepatol. 2010;4(1):51-61.
© 2010 Expert Reviews Ltd.
Abstract and Introduction
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.
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. 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.
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.
Origin of HCV Infection in Children: Mother-to-child Transmission
Hepatitis C is an asymptomatic disease in infants. The only efficient method for its detection is the investigation of children at risk. Infants of women with hepatitis C should be tested for HCV RNA on two occasions, between the ages of 2 and 6 months, and again at 18 to 24 months, along with serum anti-HCV.[3–5] Variants to this schedule are also employed. Tests performed in umbilical cord or before 1 month of age give a high rate of false-negative and false-positive results and are not recommended.
The offspring of anti-HCV-positive mothers have anti-HCV antibodies in their blood as a result of passive transplacental transfer. These antibodies remain detectable in the infant for the first 12–15 months of life. The definition of mother-to-child transmission of HCV includes: the detection of anti-HCV antibodies in a child over 18 months of age, or the detection of HCV RNA in a child over 2 months of age, preferably confirmed in two different samples.
Children born to anti-HCV-positive and HCV RNA-positive mothers have an infection risk of 4–10%, with no differences between caesarean or vaginal delivery, or between children who are breastfed or receive infant formulas.[3,6] Once pre- or peri-natal transmission has been discarded, cohabitation of the child with the mother entails no appreciable risk.
Excellent reviews on HCV vertical transmission are available.[3,6,7] Some risk factors have been clearly identified, such as maternal viremia[4,8] or maternal co-infection with HIV-1. Maternal intravenous drug use, the presence of HCV RNA in maternal peripheral blood mononuclear cells and genetic factors (HLA-DRB1*10 in children) could also facilitate transmission.[9–11]
However, discordance exists between studies. Viral load in the mother is a rational risk factor involved in transmission to the child, but was found to be either high or not significantly different between transmitting and nontransmitting mothers.[8,12] Other risk factors are linked to abnormal labor, as published data support facilitated transmission by a prolonged time from rupture of membranes to birth.[6,13,14] Antiretroviral treatment of HIV-infected mothers decreases the risk of HCV transmission to levels similar to HIV-negative mothers.
Mother-to-child transmission theoretically can occur in utero, at the end of pregnancy or at delivery. Among 54 infected infants tested within 3 days of birth, 31% displayed HCV viremia, suggesting that intrauterine infection could have occurred.
There are currently no established interventions to prevent infection of the child born to an infected mother. In particular, there is no evidence to suggest that women should be offered an elective caesarean delivery or be advised to avoid breastfeeding.
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. 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.
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. 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.
Genotype influences clearance rates. Children with genotype 3 infection had the highest ALT levels and the highest rate of spontaneous viremia clearance. 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.
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]
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).
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%). The viral load does not appear to be correlated to ALT levels or the histologic lesions.
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.
In a later report with additional children (total of 112 cases) fibrosis was assessed by the METAVIR scale. 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 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
Severe Liver Disease in Children
In a series of 332 persistently viremic Italian children, who were otherwise healthy, six patients (1.8%) with high ALT levels developed signs and symptoms of advanced liver disease (asthenia, epistaxis, pruritus, ascites and gastrointestinal bleeding). Two patients developed decompensated liver disease at a very young age (2 and 5 years, respectively); however, most cases of advanced disease were older (age 11–15 years). Genotype 1a was involved in five cases. None of these children had a history of drug or alcohol abuse, nor were they obese.
Decompensated liver disease was observed in one out of 194 (0.5%) children included in a multicenter European study. This patient had a history of blood transfusions for hemolytic–uremic syndrome at the age of 3 years. Liver transplantation was needed when he was 19 years of age. The infection was due to HCV genotype 1a, and liver–kidney microsomal antibody type 1 (LKM1) was found to be positive.
LKM1 antibodies are detected in 6–10% of children with chronic HCV infection. Overall, features of these patients help to differentiate them from those with autoimmune hepatitis. Coexistence of LKM markers was associated with a higher than expected rate of significant fibrosis (Ishak score >3 in 27%) in a series comprising 21 patients.
Other cases of severe liver disease in childhood have been reported occasionally. A quaternary referral center in the USA described seven cases (7.7% of 91 referred patients) aged 4–18 years old (mean 11 years). Other authors reported two 14-year-old adolescents, one of them without comorbid conditions, with cirrhosis and hepatocellular carcinoma.
The small proportion of children with chronic hepatitis C leading to liver failure is confirmed in liver transplantation registries, as HCV comprises less than 1% of the indications in children. Among 63 cumulative pediatric cases (1988–2005) undergoing transplantation for HCV end-stage disease in the USA, 88% were over 10 years old.
Outcomes in Adult Age
An assessment of the characteristics of liver disease in adults who acquired HCV infection in childhood is available for certain populations of patients. Overall, patients who acquired HCV by parenteral routes predominate, and many were affected by transient or persistent conditions that may influence outcome. A report on 11 patients infected at birth by the same blood donor found, by the age of 35 years, nine cases with no fibrosis or mild fibrosis and one each with discrete (Ishak 3) or marked (Ishak 4) fibrosis. Similar findings were obtained in children who acquired HCV infection after cardiac surgery, and in a series of leukemia survivors.
Since there are no prospective studies on the course of the infection from infancy to adulthood, the data provided by studies in adult patients are of interest. In these studies, infections beginning before 40 years of age presented a severe liver disease rate of only 2–8% after 20 years, while infections developing after age 40 years yielded a 20% cirrhosis rate after 20 years. The estimation of the percentage of patients that develop severe disease in the course of a lifetime varies according to the different studies. In the period of 20 years after first infection, 20% of the patients seen in referral centers developed cirrhosis, although in the case of patients identified through screening of the general population or blood donors, only 4–7% were found to have cirrhosis.
There are different approaches to the treatment of children with chronic hepatitis C. The main characteristic of chronic hepatitis C is its persistence over time with slow progression to fibrosis. Severe disease is rare in children, and therefore follow-up without treatment until adult life is a valid option for most pediatric patients. Treatment during childhood does not achieve increased rates of response compared with adult patients and adverse effects are frequent and, even in some cases, may be severe. Conversely, treatment may be justified, since it allows definitive resolution in a subgroup of patients. Quality of life is not affected in children with HCV infection, but parents are worried about the outcome and perceive the difficulties of social life, even when there is a negligible risk of horizontal transmission.[43,44] Adolescence and young adulthood are associated with high scholar or work demands, and more difficult compliance with medical visits. All those factors may lead to postponed treatment.
The decision to treat should consider several aspects in the individual patient: age, severity of disease, efficacy of the chosen therapy, its adverse effects, compliance to treatment and willingness. Children under 3 years old are not eligible for treatment (and treatment is not approved), as HCV infection may still spontaneously resolve and spastic diplegia has been reported in infants treated with IFN-α for hemangiomas.
Over time, and in parallel with the results obtained in adults, experience has been gained in children with IFN-α monotherapy,[46–50] the combined use of IFN-α and ribavirin,[51,52] pegylated IFN (PEG-IFN) monotherapy and, at present, the use of PEG-IFN with ribavirin, which was approved by the US FDA (in December 2008) and the EMEA (in December 2009) for children older than 3 years of age.
Baseline Patient Evaluation
Patients are excluded if they have comorbid medical conditions (i.e., moderate or severe depression, psychiatric conditions, seizures and renal insufficiency) that could compromise the tolerability of the drugs. Patients testing positive for autoimmunity markers – antinuclear antibody, smooth muscle antibody and LKM1 – are enrolled if other features do not suggest autoimmune hepatitis. Adolescents should be instructed in birth control during antiviral therapy and for 6 months after treatment cessation. Routine pregnancy testing is advised in girls of child-bearing potential.
The viral genotype involved must be known in order to assess the probability of response and to design the duration of therapy. Viral load must be quantified since the decision to maintain therapy will depend on the course of viraemia at week 12 of treatment in the case of genotypes other than 2 and 3. A biopsy is recommended before starting treatment. According to several studies performed on pediatric chronic HCV infection histology, showing mild lesions in most, the need for a biopsy to assess the disease is controversial, although it is the only method to identify severe cases. However, treatment decisions should not rely on histological findings.
Further workout should be carried out, especially in line with recent observations of genetic polymorphisms linked to response to treatment, which can be of value for treatment decisions in the future. Candidate studies are polymorphisms near the IL28B gene, encoding IFN-λ-3, which has been associated with an approximately twofold change in response to treatment.
Common terminology refers to 'rapid viral response' when viremia turns undetectable in week 4 of treatment, 'early viral response' when HCV RNA is negative in week 12 and 'end of treatment response' when viremia proves negative at the end of treatment. Sustained virologic response (SVR) is defined as undetectable serum HCV RNA 24 weeks after treatment cessation and is equivalent to resolution of infection.
In treatment-naive patients, the likelihood of achieving a SVR is best predicted by a more than 2 log10 unit decrease in HCV RNA by 12 weeks of therapy. Among naive populations, less than 2% of patients who fail to achieve an early virological response ultimately achieve a SVR.
Therapy aims to achieve negative conversion of HCV viremia to below the detection limit of the qualitative PCR technique employed (30–50 IU/ml). Once negativity has been achieved, treatment must continue long enough to ensure eradication of the infection in the liver. Different HCV genotypes exhibit different sensitivities to treatment. Genotypes 2 and 3 are more sensitive, with healing rates of 83–100% of all patients treated for 24 weeks. In the case of genotypes 1 and 4, the overall SVR rate is 50%, and 48 weeks of therapy are required. The high probability of a favorable response in the case of a sensitive genotype means all patients need treatment for 24 weeks. In the case of less-sensitive genotypes, re-evaluation is carried out after 12 weeks. If at this point there has been a decrease in viral load of at least 2 log10, treatment is continued up to 48 weeks. However, if such a decrease in viral load is not found, treatment is withdrawn, since healing is not likely to occur even if the full treatment course is administered.
Guidelines of treatment are well established in adults. In these patients current studies aim to shorten the duration of therapy (to 16 weeks in the case of a sensitive or favorable genotype, and to 24 weeks in the case of genotype 1) for those subjects with rapid viral response, and to prolong therapy (48 weeks for genotype 3 and 72 weeks for genotype 1) for those subjects showing a drop in viremia, but with persistent positive HCV RNA at week 12. Other ongoing investigations aim to increase efficacy by adding antiviral agents, such as telaprevir or boceprevir, to the conventional PEG-IFN plus ribavirin treatment.
Pegylated IFN-α Pegylated IFN-α is created by covalently linking a polyethylene glycol moiety to the IFN-α protein. The addition of this moiety to IFN-α confers an extended serum half-life compared with native IFN-α, allows once-weekly dosing and significantly improves SVR rates. Two forms of PEG-IFN have been developed, PEG-IFN-α-2b and PEG-IFN-α-2a. PEG-IFN-α-2a uses a large (40 kD) branched polyethylene glycol molecule, while PEG-IFN-α-2b uses a smaller (12 kD) linear molecule. The overall results from controlled trials in adults suggest that they achieve a similar rate of SVR.
Adverse events of PEG-IFN occur in the same proportion of patients and are of the same quality as observed with IFN-α. PEG-IFN is more convenient because of the weekly administration and influenza-like symptoms being limited to one versus three doses per week with conventional IFN.
Dosing in Children A once-weekly dose of PEG-IFN-α-2a is calculated from each patient's body surface area according to the formula BSA (m2)/(1.73 m2) × 180 µg. This dosing achieves adequate therapeutic concentrations.
PEG-IFN-α-2a 1–1.5 µg/kg once a week has been given to children after approval in adults. Another approach is to adjust the adult dosing of 1.5 µg/kg to the body surface of the child, so dosing for children results in 60 µg/m2 per week.
The PEG-IFN-α dose is transiently decreased in patients with a neutrophil count of less than 1–1.25 × 109 cells/ml to avoid significant neutropenia. PEG-IFN-α is temporarily discontinued if the neutrophil counts fall below 0.75–1.00 × 109 cells/ml; and it is resumed once the neutrophil counts recover.
Ribavirin Ribavirin is a guanosine analog. Ribavirin alone has a relatively minor antiviral effect in HCV-infected patients, but in combination with PEG-IFN-α it appears to enhance the second and third phases of viral decay, thereby reducing the chance of relapse. Its suggested mechanisms of action include error catastrophe resulting from mutagenesis via incorporation of ribavirin into HCV RNA during replication, direct inhibition of HCV RNA replication, inosine-monophospatedehydrogenase inhibition and immunomodulation. A relationship between ribavirin dose and response to therapy with both IFN-α-2a and -α-2b has been established, especially in patients with HCV genotype 1.
Ribavirin is cleared by the kidneys, so it should be reduced in patients with decreased creatinine clearance and completely avoided in renal insufficiency. Its main toxicity is hemolytic anemia, directly related to the concentration of ribavirin in erythrocytes. Anemia is the most common reason for ribavirin dose reduction or treatment discontinuation.
Dosing in Children A study in children receiving IFN-α-2b plus ribavirin 8, 12 or 15 mg/kg/day demonstrated that those on 15 mg/kg had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12, with an acceptable safety profile.
On-therapy Assessments in Children
For assessment of efficacy, HCV RNA titers are measured at weeks 4, 12, 24 and 36, at the end of treatment, and every 12 weeks for another 6 months after the end of treatment. The assessment of safety should be planned in order to promptly detect adverse effects that require dose adjustment. Drugs cause influenza-like symptoms, neutropenia, anemia and weight loss especially during the first month of treatment. Clinical and analytical follow-up is performed every 2 weeks in the first phase of therapy. Monthly visits are advisable up to the sixth month, and scheduled every 3 months for the remaining period of treatment and for another 6 months after the end of treatment. Depression, thyroid disorders and growth velocity should be assessed. The long-term effects on thyroid function (if disturbed during treatment) and on growth would require an extended time (i.e., 2 years) of follow-up.
Efficacy of PEG-IFN Plus Ribavirin Treatment in Children
Combined therapy with PEG-IFN and ribavirin has improved sustained response rates compared with other treatments and currently represents the standard therapy in adult patients.
There are two ongoing trials in children with almost finished efficacy reports.[58–60] One international study investigates the pharmacokinetics, efficacy and safety of PEG-IFN-α-2b 60 µg/m2/week combined with ribavirin 15 mg/kg/day in 107 children. Another multicenter North American trial investigates PEG-IFN-α-2a plus ribavirin (55 children) compared with PEG-IFN-α-2a monotherapy (59 children) (Table 2).
Two European studies have been published with the data on the efficacy and adverse effects of the PEG-IFN plus ribavirin combination in children. One was conducted in a center in Spain; 30 children (24 naive) were enrolled to receive PEG-IFN-α-2a 1 µg/kg/week with ribavirin 15 mg/kg/day. The other trial was carried out in several centers in Germany, and 61 children (51 naive) were given PEG-IFN-α-2a 1.5 µg/kg/week plus ribavirin 15 mg/kg/day. In both studies the duration of treatment was 24 or 48 weeks in genotype 2/3 infections, and for 48 weeks in the case of genotype 1 or 4. The results were similar in both (Table 2), and showed a response equal to or slightly greater than that reported in children on conventional IFN-α given three-times per week plus ribavirin.
In the Spanish study, involving strict chronic infection inclusion criteria (over 3 years from infection), and with a patient age of 3.5–16 years, 69% of the cases were due to mother-to-child transmission, 86.6% corresponded to genotype 1, and baseline viral load was >5 log10 IU/ml in 66.6% of cases. SVR was achieved in 15 (50%) of 30 patients: in three (100%) out of three patients with HCV genotype 3, and in 12 (44%) out of 27 with HCV genotype 1. One patient with HCV genotype 4 did not respond. All patients who attained SVR remained HCV RNA-negative at further follow-up visits (up to 36 months) and had normal liver function.
In the German study, the patients were between 2–17 years of age; 40.3% of the infections were the result of vertical transmission and 75.8% presented genotype 1. Of 46 patients with genotype 1, 22 (47.8%) showed SVR. All individuals with genotype 2 or 3 (n = 13) responded permanently, irrespective of the duration of treatment (i.e., 24 or 48 weeks) (p < 0.0003). One of two patients with genotype 4 had SVR.
Predictors of Response
The study of baseline characteristics of treated patients may help to identify predictors for response, in order to select the candidates for therapy. Among adult patients, those aged less than 40 years without advanced disease show better response rates. However, overall results of treatment during childhood do not clearly offer significantly better results compared with adults.
The most important determinants of response in children are the viral genotype and viremia levels among those with genotype-1 infection. No baseline characteristic excludes response to therapy among those with genotype 1. On the other hand, the evolution of viremia after 12 weeks of therapy is of much help to identify future responders. In practical terms, all children may be eligible for treatment and early stopping rules according to week 12 viremia should be applied.
The HCV genotype is the main baseline predictor of response. Recent unpublished pediatric trials obtained a response in 93% of genotype 2 or 3, 80% of genotype 4 and 53% of genotype 1 HCV infections, and 47% of genotype 1 compared with 80% of genotype non-1, respectively.[58,60] In the international PEG-IFN-α-2a plus ribavirin study, response in genotype 1 was influenced by baseline viral load, as those showing HCV-RNA over 6 × 105IU/ml had 29% SVR compared with 72% SVR in genotype 1 with lower titers.
Patient age does not seem to influence response (SVR: age < 12 years versus older children: 54.8 vs 63.3% in the German study and 45 vs 60% in the Spanish study). Responders show similar baseline ALT levels compared with nonresponders, and children with normal aminotransferase values display the same SVR rate as those with abnormal biochemistry prior to therapy. The baseline viral load and Knodell index did not influence the response in the Spanish study. However, in both experiences, the response in those children who developed the infection as a result of blood transfusions tended to be higher than in those with mother-to-child transmission (German children: 70.4 vs 48%; p = 0.087; Spanish children: 78 vs 38%; p = 0.1).[61,62]
Virological surveillance while on therapy appears to be the best predictor of response. In the Spanish study, only one patient showed negative HCV RNA at week 4. At week 12 of treatment, 51.7% showed undetectable HCV RNA, while 72% presented a greater than 2 log10 decrease compared with baseline viral load. A SVR was elicited in 87 and 71% of those presenting the above characteristics, respectively, at week 12. No cases with less than 2 log10 reduction at week 12 achieved sustained response. Continued therapy for 48 weeks in six children with positive HCV RNA at week 24 was ineffective in all cases.
The German study reported that 62.3% of the treated children achieved negative HCV RNA at week 12. In turn, 91% of the patients with genotype 1 and 92.3% of those with genotypes 2/3 who showed a sustained response presented undetectable viremia at week 12 of therapy.
Nonresponders to Therapy
Circumstances associated with a lack of response in children have not yet been elucidated.
Children with genotype 1 infection with mother-to-child transmission, currently representing the most numerous group, have shown SVR rates of 37.5 and 35% in the Spanish and German studies, respectively.[61,62] Thus, for many patients current therapy is inefficient.
Nonresponders can be retreated, but there is a very limited experience in children. According to studies in adults, the likelihood of response to retreatment depends on the type of response to prior therapy (relapsers achieve near 40% of SVR compared with 10% in nonresponders) and the differences in efficacy between the initial and the retreatment regimens. Very few children who failed to respond with IFN-α monotherapy were retreated with IFN-α plus ribavirin, or PEG-IFN-α-2a plus ribavirin.[61,62] Using the highest efficacy PEG-IFN plus ribavirin, a sustained response was achieved in three out of 11 cases.
The adverse effects of PEG-IFN plus ribavirin are similar to those associated with conventional IFN, involving fewer injections and immediate injection reactions. Other adverse effects were of the same nature and intensity.
The toxicity of PEG-IFN plus ribavirin treatment must be carefully evaluated. It has been assessed in only two studies.[61,62]
In almost all children and adolescents, transient flu-like symptoms with variable intensity, including moderate fever, are observed during the first weeks of treatment. In most of them, the symptoms resolved or were of minor intensity during the second 6 months. Febrile convulsions are a hazard in younger children, but the problem did not occur in available series. Dose reduction by 20–30% of PEG-IFN was carried out because of considerable leukopenia in 5% of patients in the German series. Prolonged (>1 month) or permanent reductions in PEG-IFN-α-2b doses were required in 23% of Spanish children (Table 3).[61,62]
Owing to hemolysis induced by ribavirin, mean hemoglobin levels decrease within the first week of therapy, reaching a mean maximal decrease of 1.4 g/dl by week 12. Hemoglobin values are stable during the remaining period and return to normal when therapy is discontinued or completed. No reduction in ribavirin dose was required. Reticulocyte levels increased during therapy but returned to normal thereafter.
School performance is not grossly affected. Transient changes in character or mood have been recorded in 15–30% of the children, but severe psychological impairment was not observed.[61,62] Depression is a concern and should be looked for in adolescents, as suicidal ideation and even suicidal attempts have been reported during treatment with conventional IFN-α plus ribavirin.
Patients with detectable LKM1 antibodies at baseline have shown either stable or varying titers during therapy. No patient developed LKM1 antibodies, although previous experiences have shown that LKM1 appear in 5% of children treated with IFN-α. No specific liver function events occurred in antinuclear antibody-positive or LKM1 antibody-positive patients during or after therapy. Regarding the possibility of IFN facilitating autoimmune disease, one girl was reported to have developed diabetes mellitus after 9 months of treatment; therapy was continued without changing dosage and the patient showed SVR.
The emergence of thyroid antibodies and thyroid-stimulating hormone elevation during treatment is significant. In the German study, five individuals received a weight-adjusted dose of l-thyroxine until the end of treatment. In three of these, l-thyroxine could be stopped during follow-up, and in two patients thyroid hormone supplementation was maintained 12 months after discontinuation of ribavirin and PEG-IFN.
According to the Spanish study, four patients developed antithyroid antibodies. Two patients showed sudden decreases in thyroid-stimulating hormone values during therapy, accompanied by high T4 values and weight loss. Treatment was discontinued immediately in both patients. Anti-thyroid antibodies appeared in successive checkups. No specific therapy for hyperthyroidism was required and thyroid-stimulating hormone and T4 values returned to normal. The remaining two patients developed antithyroid antibodies during therapy and the condition persisted when off therapy. Mild elevation of thyroid-stimulating hormone or T4 values was observed in another additional six patients.
Growth during the 48-week treatment period has been shown to be reduced in most patients by a mean of 1.6 cm compared with the average growth for age and gender. Growth velocity was normal in the 6-month period after the end of treatment; however, the modest decrease in height percentile observed during therapy was not recovered in the short term.
In conclusion, the efficacy of combined therapy in children warrants its application. A response rate of 50% in genotype 1 patients and more than 90% in genotype 2 or 3 patients is achieved, which means cure of a chronic disease. However, more in-depth studies are needed, with further investigation of the factors implicated in the development of thyroid alterations in some children.
Current treatment (PEG-IFN-α plus ribavirin) in children with chronic hepatitis C should be managed by pediatric specialists. Many individual and family variables determine the appropriate time to initiate treatment. Mid-childhood age before adolescence is preferable. Side effects are usually well tolerated, but severe adverse events may occur in a low number of children. The near complete efficacy in favorable genotypes, and the early stopping rules for genotype 1 cases shifts the balance toward applying treatment to children, although new drug investigation is needed. The mild disease that children usually present makes safer the initiation of studies once efficacy and toxicity profiles of new drugs have been assessed in adult patients.
New lines of research in children are necessary to assess long-term clinical outcomes, to develop noninvasive methods for detecting fibrosis, to establish gene polymorphisms related to disease progression and response to therapy and to identify individuals at risk for significant side effects before treatment initiation. Trials with combined therapy plus antivirals should begin as soon as safety profiles have been established in adult patients.
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Papers of special note have been highlighted as:
•• of considerable interest