Monday, November 26, 2012

Treatment of Chronic Hepatitis B and C in Children


Future Virology

Treatment of Chronic Hepatitis B and C in Children

Giuseppe Indolfi, Alessandro Nesi, Massimo Resti

Nov 25, 2012

Future Virology. 2012;7:955-972. © 2012 Future Medicine Ltd.

HBV and HCV are the predominant causes of chronic viral hepatitis in children and adults. The main purposes of the present review are to provide the reader with a comprehensive overview of the currently available therapies for chronic hepatitis B and C in children and to critically review the current guidelines and indications for treatment provided by the major international societies and by the consensus of expert panels. Overall, a conservative approach is generally warranted in children with chronic hepatitis B. For HCV, the high effectiveness of pegylated interferon and ribavirin in children with genotype 2 or 3 chronic infection supports the decision to treat. For genotype 1 infection the encouraging results of the use of direct antiviral agents in adults suggest a more conservative approach.

Epidemiology of Hepatitis B & C in Children
HBV and HCV are the predominant causes of chronic viral hepatitis in children and adults, [1] and are found worldwide. It is estimated that approximately 2 billion people in the world have been infected by HBV, more than 350 million are chronic hepatitis B surface antigen (HBsAg) carriers, and approximately 600,000 people die every year due to the consequences of hepatitis B. [101] Approximately 150 million people are chronically infected with HCV and more than 350,000 people die every year from hepatitis C-related liver diseases. [102] Despite these impressive figures, the epidemiology of HBV infection has changed dramatically with the introduction of universal immunization programs, [2] and the spread of both HBV and HCV infections has been significantly reduced by the implementation of blood-donor screening. [101,102] Nowadays, in endemic areas, HBV infection transmission from mother to child accounts for approximately half of the chronic HBV infections in children, the remainder being acquired through horizontal transmission during infancy and early childhood. In western Europe and North America the risk of perinatal transmission of HBV is low due to active and passive immunization strategies, but it is still present in infants born to mothers with HBV DNA levels >20 million IU/ml, in whom immunoprophylaxis and/or immunization is not always effective. [3] In developed countries, the majority of HBV infections are transmitted during young adulthood by sexual activity and injecting drug use. [101] However, pediatricians are facing an increasing number of HBV-infected children adopted or moved from countries with higher prevalence of HBV infection. [4] The leading source of HCV infection in children is transmission from the mother to the child. [5] Horizontal intrafamilial transmission of HCV has been demonstrated but whether horizontal transmission makes any significant contribution to the burden of HCV infection is still controversial and data about epidemiology and routes of horizontal transmission are uncertain. [6]

The Infection
HBV infection during early childhood results in a high rate of chronic infection when compared with adults. [8–10] Chronic infection is usually defined as an individual remaining positive for HBsAg for 6 months or longer. Chronicity rate has been estimated to be 90% for newborns, 25–30% for children less than 5 years of age and less than 5% for adolescents and adults. [8–10] From the clinical point of view, chronic hepatitis B in children is often asymptomatic and it is a mild disease. [11,12] Children with chronic hepatitis B are expected to be healthy with no clinically detectable sign of liver disease. [11,12]
Different phases of chronic hepatitis B can be defined according to HBV serologic markers and HBV DNA detection by PCR. [13] The meaning of HBV serologic markers is summarized in Table 1 and a rapid overview of the different phases of chronic hepatitis B is provided in Table 2 . The first phase of chronic hepatitis B, known as the immune-tolerant phase, is characterized by high viral replication (high HBV DNA), positive hepatitis B e antigen (HBeAg), normal aminotransferases and little liver damage on liver biopsies. [13] The exact duration of this phase is unpredictable but it is affected by the route of HBV infection (it occurs earlier and more frequently in subjects who acquired HBV horizontally than in those infected perinatally), [14] by environmental factors such as nutritional status, and by viral genotype (HBV genotype C infection is associated with delayed spontaneous seroconversion). In different studies around 90% of children less than 15 years of age are still HBeAg positive and only a minority of the children infected perinatally spontaneously enter the second phase before puberty, known as the immune-active phase. [14] In the immune-active phase, aminotransferases are elevated and HBV DNA levels start to decrease. It is noteworthy that in this phase active inflammation can be found in the liver with necrosis of the parenchyma that can develop into fibrosis over time. [15] The immune-active phase leads to spontaneous HBeAg/anti-HBe seroconversion in most of the patients preceding entry into the inactive carrier phase. A fraction of patients retain hepatic inflammation despite HBeAg/anti-HBe seroconversion, with elevated aminotransferases and high HBV DNA, and remain in the immune-active state with a greater risk for the development of cirrhosis and hepatocellular carcinoma (HCC). [13,14] The inactive carrier phase is characterized by normalization of aminotransferases, absent or low viral replication, with low (<2000 IU/ml or <10 4 copies/ml) or undetectable HBV DNA and inactive liver histology. [13] Regression of liver fibrosis has been described in inactive carriers. [13,14] In long-term longitudinal studies, around 15% of inactive carriers became anti-HBs-positive, marking the resolution of HBV infection. [11,12] In these patients the overall prognosis is good if cirrhosis has not developed before anti-e and anti-s seroconversion. [16] It should be noted that low-level HBV replication with detectable HBV DNA in the liver may persist in patients who become anti-HBs positive. [17] Among inactive carriers few patients (5%) can experience the selection of precore mutants leading to anti-HBe-positive/HBeAg-negative chronic hepatitis with persistent viral replication, abnormal aminotransferases and histologically active hepatitis. [13,14] The precore mutation, a G3A mutation at codon 1896 that results in the occurrence of a stop codon, makes the virus unable to code for HBeAg, leading to HBV replication uncontrolled by the host's immune system. There is overwhelming evidence from different studies that basal core promoter mutations are independent risk factors for the development of active liver disease and HCC. [13] Finally, in inactive carriers, reactivations characterized by a rise in HBV DNA, high aminotransferase levels, hepatic necro-inflammatory changes on liver biopsies with or without reverse seroconversion to HBeAg and HBsAg positivity are possible, especially under immunesuppression. [18] HBV reactivation may be explained by the persistence of low-level HBV replication in the liver [17] and/or by the presence of covalently closed circular DNA in the nucleus of infected hepatocytes. [19,20]

Fibrosis, Cirrhosis & HCC
During childhood and adolescence but before adulthood, 1–5% of HBeAg-positive individuals develop cirrhosis and some of them develop HCC. Studies from single centers from different geographic areas showed that around 2% of children with chronic hepatitis B develops HCC. [11,21] This value might have been impacted by the referral nature of the centers involved in the studies. Necroinflammatory changes on liver biopsies and fibrosis development are typical of patients in the immune-active phase, of patients with anti-HBe-positive/HBeAg-negative chronic hepatitis and of patients with hepatitis B reactivation. [13,14,18] In the immune-tolerant phase, liver biopsy usually shows only minimal inflammation with no or minimal fibrosis. Hepatic inflammation is also minimal or absent in the inactive carrier phase, and inactive carriers with no signs of cirrhosis at anti-HBe seroconversion did not show any progression to cirrhosis over 24–29 years of follow-up. [11,12] The risk of development of cirrhosis and HCC is correlated to the degree of liver fibrosis accumulated in the immune-active phase. [11,21] Studies in adults suggest that the longer the immune-active phase is, the higher the risk of fibrosis and its complications. [22–24] HCC development is strictly correlated to the presence of cirrhosis, but other specific risk factors have been identified. The risk of HCC in children, for example, is higher in males when compared with females, is dependent on viral genotype and is increased in children with early anti-e seroconversion. [11,21] During the inactive carrier phase even patients without active liver inflammation and fibrosis are at risk of developing HCC over time. This ongoing risk of HCC may be a consequece of the presence of HBV DNA integrated into the host's hepatocyte DNA due to the reverse transcriptase properties of the HBV polymerase gene. It has been hypothesized that integrated HBV DNA may trigger genomic mistakes during hepatocyte cell division that might result in HCC. [25] The presence of persistently high levels of HBV DNA over the years during the immune-tolerant phase likely provides an accumulation of integration sites, increasing the risk of HCC over time. [26]

Achieving Optimal Treatment & the End Points of Currently Available Therapeutic Options
Understanding the natural history of chronic hepatitis B in children is crucial to delineate the characteristics of the ideal treatment for the infection. For chronic hepatitis B the risks of treatment must be weighed against the benefit demonstrated beyond the baseline natural history. [27] As already mentioned, children with chronic infection are asymptomatic and have a good quality of life. [11,12] Although rare, the primary adverse outcomes of chronic hepatitis B in children are cirrhosis and HCC. Cirrhosis and HCC are strictly dependent on one other, and are dependent on the amount of liver fibrosis and on the presence of HBV DNA integrated in the host's DNA. As a consequence, the optimal treatment for chronic hepatitis B in children: should be started as early as possible during the immune-tolerant phase (when HBV DNA is high and aminotransferases are normal) and before the immune-active phase (when fibrosis first accumulates), avoiding or reducing to a minimum the degree and the duration of liver inflammation; should be effective in eradicating HBV as soon as possible, reducing the risk of integration of HBV DNA in the host's DNA; and should result in HBsAg loss, a target infrequently achieved in untreated chronic infections and infrequently achievable with the currently available anti-HBV agents. So far, the goals of the currently available therapeutic options are to obtain the highest degree of virological suppression, leading to biochemical remission, histological improvement and prevention of complications. [13,28]

Therapeutic Options
In the USA five drugs are approved for treatment of chronic hepatitis B in children (individuals younger than 18 years old): two nucleoside analogs, entecavir (approved for children older than 16 years of age) and lamivudine (approved for children older than 1 year of age), two nucleotide analogs adefovir dipivoxil and tenofovir disoproxil fumarate (approved for children older than 12 years of age) and interferon α-2b (approved for children older than 1 year of age). Table 3 summarizes currently available treatments for hepatitis B and their approval based on patient age. The rationale underlying the use of interferon or of nucleos(t)ide analogs is different. Interferon (or pegylated interferon in adults) acts as an immune stimulator. Interferon is administered in noncirrhotic patients for predefined durations with the aim of inducing immune-mediated control of HBV infection with the opportunity to obtain a sustained virological response (SVR) off-treatment. [13,28] The major advantage of interferon is the virtual absence of viral resistance, but it has only a moderate antiviral effect, it requires subcutaneous injection and its use carries the risk of adverse events. [13,28] Nucleos(t)ide analogs are HBV inhibitors of varying potency and can be used for treatment of finite duration with or without interferon to obtain sustained off-treatment virological response or for long-term treatment to reduce and control HBV replication. [13,28] It should be noted that treatment duration is unpredictable prior to therapy with nucleos(t)ide analogs as it depends on the timing of anti-HBe seroconversion and its persistence off-treatment. Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance, while telbivudine, adefovir and lamivudine have a lower barrier to resistance. HBV resistance to nucleos(t)ide analogs is characterized by the selection of HBV variants with amino acid substitutions that confer reduced susceptibility to the administered drug and possibly to other nucleos(t)ide analogs. HBV strains that harbor the rtA181T/V lamivudine resistance mutation, for example, have a diminished response to adefovir. Management of drug-resistant chronic HBV infection in children is a challenge due to the limited number of drugs labeled for pediatric use. Furthermore, a child harboring a resistant HBV strain will also have fewer effective treatment options as an adult. In patients being treated with one nucleos(t)ide analog showing evidence of virologic breakthrough (i.e., HBV DNA is detectable or increasing), different options are available such as stopping the treatment with careful monitoring of the child, adding another drug (adefovir to lamivudine) and switching to interferon or to another nucleoside analog (from lamivudine to adefovir or, for children older than 16 years, from adefovir to entecavir). While the risk of resistance, together with the unknown long-term safety profile of these drugs are the major disadvantages of nucleos(t)ide analogs, it should be noted that their oral administration, good tolerance and overall higher antiviral effect when compared with interferon make their use particularly suitable for children. So far well-performed randomized placebo-controlled trials for children with chronic hepatitis B have been performed using interferon-α2b, [29] lamivudine [30] and adefovir. [31] The primary efficacy end point of these studies was virologic response, a composite measure defined by the reduction of serum HBV DNA to undetectable levels and by the loss of serum HBeAg and/or by the normalization of aminotransferases. The main results of the previously mentioned trials are summarized in Table 4 . These studies show that treatment response is associated with higher baseline aminotransferases, lower baseline HBV DNA levels and high baseline histology activity index scores, supporting the concept that the current available therapies accelerate the spontaneous course of infection in children with greater disease activity and lower levels of replication. In all the trials seroconversion rates to anti-HBe in HBV carriers with normal liver enzymes do not differ in treated and untreated subjects. Interestingly, in the interferon-α2b trial [29] the rate of HBsAg clearance was significantly greater (25%) in children who responded promptly to treatment than in late responders, nonresponders or untreated controls.
Four studies in children investigated the combination of lamivudine with interferon-α in treatment-naive children with elevated aminotransferases. [32–35] The combined therapy seemed to be associated with virological response rates similar to those obtained with monotherapies but appeared to be protective against the emergence of mutations. These data need to be confirmed by large clinical trials. 

Guidelines on Management of Children With Chronic Hepatitis B & Consensus of Expert Panels
Practice guidelines on the management of adults and children with chronic hepatitis B have been published by the major international societies. [13,28] Decisions regarding the selection of children to treat, appropriate timing of treatment and choice of antiviral therapy are complex. Recently, different panels of pediatric liver specialists have published their comprehensive consensus, yielding similar results. [36,37] The main message thus far is that a conservative approach is generally warranted in children with chronic hepatitis B until more clinical data and therapeutic options are available. In the immune-tolerant phase there is no indication for treatment except in the context of a clinical trial. Immune-tolerant children are less likely to respond to currently available treatment and there is a very high risk of development of drug resistance. Children in the immune active phase with persistently elevated aminotransferases (more than two-times the upper limit of normal) and evidence of active viral replication (HBeAg seropositive, and/or HBV DNA levels >10 5 copies/ml or 20,000 IU/ml in their serum) for more than 3–6 months should be considered for therapy. [36,37] The American panel suggests that the decision to treat could be guided by the family history of liver disease, especially HCC, or by the results of liver histology. [37] The latter indication, however, should be evaluated critically as liver biopsies will demonstrate near-normal histology for most of the children with chronic hepatitis B, while only a real minority will show significant fibrosis or high-grade inflammation. [11,12] The panel of the European and of the North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition argued that treatment can be delayed in the immune-active phase for an observation period of at least 3 months if acutely elevated aminotransferases, are particularly high (more than five-times the upper limit of normal) and if there is no concern about hepatic decompensation. [36] There is good agreement in considering indicated treatment in patients with reactivations, even though this indication derives from extrapolation from adult studies. [18] Overall, interferon is considered the agent of choice. Nucleos(t)ide analogs are secondary therapies, and children who receive these agents require careful monitoring for development of resistance. There is a significant need to run large clinical trials to evaluate, as has already been done for HIV and HCV infection, the efficacy of combination treatment for chronic hepatitis B in children.

HCV Infection
The Infection
Perinatal transmission is the most frequent route of HCV infection in children. [5] Approximately 20% of perinatally infected children undergo spontaneous clearance of HCV RNA in the first 5 years of life, with subsequent normalization of aminotransferase levels. [38,39] Over half of those children who undergo this spontaneous clearance of infection are infected by HCV genotype 3, and develop an aminotransferase peak at the onset of the infection. [39] For those children who do not undergo clearance, chronic HCV infection usually persists into adulthood. [39,40] Various studies have estimated that the cumulative probability of chronic progression is approximately 80%, [38,39] although children with chronic hepatitis C are often asymptomatic. [38,39] In Europe, a large, multicenter, prospective study of children born to HCV-infected mothers provided data demonstrating that, for 10% of the cohort, hepatomegaly was the only clinical symptom reported. [38] Changes in the patterns of aminotransferase levels observed in chronically infected children vary, but sustained cytolysis is observed in almost half of this group during follow-up visits. [39,41–43] Cirrhosis is rarely seen in children without underlying disorders (<2%) and HCC is anecdotal. There have been reports of severe chronic hepatitis C outcomes in certain groups of child patients that have received multiple blood transfusions, such as those with bleeding disorders or thalassemia. [44] In the largest pediatric observational study, which included both babies with perinatal infection and children who had become infected parenterally, most of whom remained untreated, the persistent viral replication associated with chronic infection was shown to result in end-stage liver disease in a small subgroup (>3%). This subgroup was characterized by perinatal route of infection, HCV genotype 1a, and maternal drug use. [40] Another group presented a small case series of cirrhosis in children that seems to provide evidence to support the suggestion that the perinatal route of infection is more likely to lead to the development of cirrhosis in children than transfusion into children with no underlying systemic disease. [45–48] In general, the chance of liver fibrosis seems to increase either with patient age, or disease duration, or both. Although data are discordant, older adolescents and young adults tend to have more severe fibrosis than children. [49–52]
The production of liver–kidney microsomal antibodies is an aspect of the host–virus interaction in chronically HCV-infected children that affects the progression of HCV-related liver damage particularly seriously. This type of antibody is not commonly found in adults, but can be detected in approximately 7% of chronically HCV-infected children. [53] These children tend to show significantly more severe liver histology findings. [53] As in adults, recent data have demonstrated that in chronically HCV-infected children, steatosis is associated with increased fibrosis severity and decreased interferon-α treatment response. [54] Health-related quality of life is an important health outcome that provides a significant input into the process of healthcare decision-making for chronically HCV-infected adults. It was recently demonstrated for the first time that asymptomatic chronically HCV-infected children experience a significant reduction in both physical and psychosocial health compared with uninfected children. This effect extended to almost all areas of health, most significantly as a reduction in parental assessment of the overall health of their child and the impact of the child's health in terms of parental distress and additional time needed to care for the child. [55] A larger analysis indicated that chronically HCV-infected children had a similar overall health-related quality of life, but demonstrated inferior cognitive functioning than their noninfected peers. [56] Additionally, the caregivers of children included in this study were more distressed about their children's medical circumstances compared with a normative sample. [56]

Treatment for Chronic Hepatitis C in Children
HCV therapy in children is based on data from adult trials, both early and continuing. In recent years two major advances have changed the therapeutic approach to chronic hepatitis C in adults: the development of direct-acting antiviral agents and the identification of single-nucleotide polymorphisms such as those located upstream of the IL28B (IFN-λ3) gene associated with spontaneous and treatment-induced clearance of HCV infection. [57] The currently recommended therapy of chronic HCV infection in treatment naive adults, is for genotype 1, the combination of boceprevir or telaprevir with pegylated interferon-α and ribavirin, [57] while for other genotypes is pegylated interferon-α and ribavirin. [58]Table 5 summarizes currently available treatments for chronic hepatitis C and their approval based on patient age. Boceprevir and telaprevir are direct-acting antiviral agents and work as NS3/4 protease inhibitors. So far no data are available in children regarding the use of direct-acting antiviral agents. IL28B genotype is a strong pretreatment predictor of virological response to pegylated interferon-α and ribavirin as well as to protease inhibitor triple therapy in adults with HCV genotype 1 chronic infection. Preliminary results confirm that IL28B genotype is a significant pretreatment predictor of response to therapy in children. [59]
The availability of original data on monotherapy with interferon-α in children is limited, as is data on the combined use of interferon-α and ribavirin and on monotherapy with pegylated interferon-α in this population. The use of pegylated interferon-α has significantly changed the approach to treatment of chronic hepatitis C in children. The half-life of interferon-α can be increased by the addition of polyethylene glycol, allowing a reduction in dose frequency to once-weekly and reducing its volume of distribution while leading to more sustained plasma levels, with the overall effect of improved viral suppression. This weekly dosing of pegylated interferon-α is generally more acceptable than thrice-weekly dosing of nonpegylated interferon-α, but especially so in children, a population that is often more sensitive to the need for regular subcutaneous injections. Combined treatment with pegylated interferon-α2b and ribavirin was approved by the US FDA in December 2008 and by the European Medicines Agency in December 2009 for children aged 3 years and older, while the use of pegylated interferon-α-2a was approved by the FDA in August 2011 for children aged 5 years and older. At present, combination therapy with pegylated interferon-α and ribavirin seems to be the most effective and safe treatment option for HCV-infected children.

Combined Treatment With Pegylated Interferon-α & Ribavirin
There have not been many studies examining the effectiveness of combined treatment with subcutaneous pegylated interferon-α-2a or -2b and oral ribavirin in chronically HCV-infected children. [52,60–63] There have only been five major well-performed trials evaluating the efficacy of this therapy. [52,60–63] As Table 6 shows, two of the five studies explored combination therapy with pegylated interferon-α-2a and ribavirin, [52,63] while the others examined combination therapy with pegylated interferon-α-2b and ribavirin. [60–62] Information regarding the doses of pegylated interferon-α and ribavirin used in the different studies, the duration of treatments and the schedules of clinical evaluations and laboratory tests for the assessment of safety and efficacy is summarized in Table 6 . Table 7 summarizes the most commonly accepted definitions of the responses to treatment. The primary end point in all the studies was the SVR rate, defined as undetectable plasma HCV RNA 24 weeks after the end of treatment. [52,60–63] Biochemical response (defined as the normalization of serum aminotransferases) was only selected as an end point in some of the studies. [60–62]

Sustained Virological Response
SVR rates in the five studies are summarized in Table 8 and range from 50–68%. [52,60–63] It is important to note that the differing genotype distributions, among other determinants of SVR, mean that SVR is not a representative result of a trial and that direct comparison of the results of different trials cannot be based on this measurement.

Significant Predictors of SVR
The role of different factors as predictors of SVR are reported in Table 9 . Results from the Peds-C trial can be evaluated only partially as only cumulative data of patients treated with pegylated interferon and ribavirin and pegylated interferon and placebo have been reported. [52] The viral genotype, [60,62,63] the viremia levels among patients with genotype 1 infection [62] and the HCV RNA status at treatment week 4 (rapid virological response, RVR) [62] and week 12 (early virological response, EVR) [61,62] have been shown to be predictive of SVR in those children receiving combined treatment. As expected given the results from adult studies, individuals infected with HCV genotypes 2 or 3 showed significantly higher rates of virological response than those of individuals infected with other genotypes. [60,62,63] A recent study that enrolled 12 adolescents infected with HCV genotype 4 treated with pegylated interferon-α-2b and ribavirin observed SVR in 75% of the individuals treated. [64] Examining the effect of route of HCV infection, the study by Jara et al. suggested that treatment was more effective in parenterally-infected patients. [61] However, this result did not demonstrate statistical significance, probably owing to the limited number of patients enrolled. [61] A study by Wirth et al. in 2005 showed a similar trend. [60] In Wirth et al.'s 2010 study, SVR was shown to be significantly higher in those HCV genotype 1 patients with baseline viral loads <600,000 IU/ml than in those with baseline viral loads >600,000 IU/ml (72 vs 29%; p = 0.0006). [62] Another study by Jara et al. showed that EVR (defined as HCV RNA-negative status at week 12 and >2 log 10 decrease in viral load at week 12), was predictive of SVR. [61] Returning to Wirth's 2010 study, RVR and EVR were shown to be strong predictors of SVR. [62] Overall, among HCV genotype 1-infected patients, 89% of those with RVR and 84% of those with EVR attained SVR. [62] In the Peds-C trial the positive predictive value (probability of SVR given earlier response) was 100% for those who achieved RVR and 65% for those who achieved EVR. [52] In adult patient populations, younger age has been associated with improved response rates, although pediatric studies do not seem to indicate an influence of age on response. [52,60–63] The studies by Wirth et al. published in 2005 and 2010 [60,62] and the study by Jara et al. seemed to suggest that adolescents had better responses, but this trend did not reach statistical significance. [61] Although such potential treatment outcome-influencing factors as aminotransferases, sex and previous treatment were examined, no significant relationship was found. [52,60–63] There is a shortage of available data on the effect of continuing treatment in non responders. In the study by Jara et al., six children infected with HCV genotypes 1 and 4 were kept on therapy for 48 weeks even if test results for HCV RNA were positive at week 24 of treatment, and all six remained HCV RNA positive at the end of the treatment course. [61] The only study reporting the influence of liver histology on response to treatment was a study by Jara et al. carried out in a Spanish population that did not show any relationship between the Knodell index and SVR. [61] Overall, in the various different studies, histological examination showed homogenously low inflammatory activity and fibrosis, and therefore there cannot be a strong expectation of correlation between histological appearance and response to treatment.
Virological surveillance during the course of therapy is valuable for determining predictors of both response and non-response, the latter of which is important to identify early nonresponders in order to apply treatment stopping rules. In the study by Jara et al., no cases that failed to demonstrate EVR (i.e., those with less than a 2 log 10 reduction at week 12 achieved SVR. [61] In Wirth et al.'s 2010 study, 14 out of the 20 non-EVR patients did not achieve SVR, while six did. [62]
Children infected with HCV genotypes 2 and 3 are usually treated for 24 weeks, but some studies have prolonged this treatment for up to 48 weeks. [52,60,62] In Wirth et al.'s 2005 study, [60] eight patients infected with HCV genotype 2 and 3 were treated for 48 weeks. Since all eight demonstrated EVR, no information could be gathered concerning the effect on SVR of prolonging treatment for 48 weeks. In Wirth et al.'s 2010 study, the intention was to treat patients with genotype 3 infection and baseline viral loads ≥600,000 IU/ml for 48 weeks, but all individuals potentially fulfilling these conditions attained SVR, including eight out of nine individuals who were treated for 24 weeks. [62] Unfortunately, there is no information available on the one patient treated for 48 weeks, such as whether or not EVR was achieved. Likewise, the Peds-C trial does not provide any data on the efficacy of treatment of patients infected with HCV genotype 2 infection for 48 weeks instead of 24. [52]

Viral breakthrough (that is, the reappearance of HCV RNA in serum while still on treatment) was a common occurrence in these studies ( Table 8 ). It is interesting to note that, across all of these different studies, all the patients who experienced these relapse events were infected with HCV genotype 1.

Adverse Events
The most common adverse events reported in pegylated interferon-α/ribavirin combination therapy studies are listed in Table 10 , while Table 11 reports reasons for dose reduction and the discontinuation of treatment. [52,60–63] Almost all of the children enrolled experienced at least one mild adverse event. [52,60–63] Flu-like symptoms, including fever, decreased appetite, asthenia and fatigue, were usually observed usually early on in the course of treatment, and either resolved or became milder in the second 6 months for most patients. [60–63] It is possible for untreated children with chronic HCV infection to develop nonautoimmune thyroid disease, [65] and across the different studies significant thyroid-related effects were observed during treatment, such as the emergence of antithyroid antibodies, the elevation of thyroid-stimulating hormone, and hypothyroidism requiring substitutive therapy ( Table 10 ). [60–63] These thyroid function and hormone abnormalities and antithyroid antibodies resolved in most patients after cessation of treatment, and in cases where levothyroxine treatment had been started, this could be discontinued. [52,60] Hyperthyroidism [61] and thyrotoxicosis [63] were reported as reasons for discontinuing treatment in three patients ( Table 11 ).
Anemia, leukopenia and neutropenia were common both as side effects and as reasons for dose reduction or treatment discontinuation. ( Table 9& Table 10 . [52,60–63] Mean hemoglobin levels were often observed to decrease in the first 6 weeks of treatment, after which point they would stabilise but remain lower than normal until cessation of treatment. Leukocyte and neutrophil counts were observed to decrease in the first 2 weeks of treatment, and would remain lower than normal at the sixth week of treatment for most patients. As with hemoglobin, these counts would then stabilise but remain lower than normal until cessation of treatment, at which point they would rapidly return to baseline levels. Median platelets counts were observed to progressively decrease below normal values in the first 12 weeks of treatment, returning to normal at 12 weeks of follow-up. The most commonly-reported gastroinstestinal symptoms were nausea, vomiting and abdominal pain, and transient behavioral changes were described in 5–40% of the patients enrolled in the available series. [52,60–63]

Growth is a major issue associated with the use of interferon treatment in children, with significant weight loss being experienced by many patients during treatment. In Wirth et al.'s 2005 study no patient lost more than 10% of their baseline weight before the initiation of therapy. [60] In the study by Jara et al., a mean decrease in body weight of 4.8% was observed by week 24, but this returned to baseline values by week 48. [61] Compensatory weight gain was described in most patients following treatment discontinuation in Wirth et al.'s 2010 study. [62] A nonsignificant weight decrease was observed at the end of treatment by Sokal et al.[63] On the other hand, Wirth et al.'s 2005 study described weight gain in 5% of the patients enrolled. [60] In terms of height, the study by Jara et al. observed that growth was reduced in 22 out of 26 patients during the 48-week treatment period, by 1.6 cm compared with the 50th percentile growth velocity for the relevant age and sex for each patient. [61] Although growth velocity returned to normal values in the 6-month period following treatment cessation, the decrease in height percentile observed during therapy was not compensated for. [61] Wirth et al.'s 2010 study described significant growth inhibition (i.e., growth velocity below the third percentile) in 70% of the patients during the treatment phase. [62] Most patients demonstrated faster than normal growth during the follow-up period, however, approximately twofold greater than during the treatment period. [62] The decrease in mean height percentile appeared to be associated with treatment duration, being greater in patients who underwent longer treatment duration. [62] The study by Sokal et al. did not observe any significant effect on height growth, [63] and follow-up height values were comparable to pretreatment height values. Recently, a follow-up study satellite of the Peds-C trial demonstrated that height-for-age z scores had not returned to baseline after 2 years of observation in many of the patients treated. [66] The long-term effects of treatment on children's growth is currently under investigation in some of the patients treated in the study published by Wirth et al. in 2010 that are currently enrolled in a 5-year follow-up study. [62] A recent study has been published on ophthalmologic complications as a satellite of the Peds-C trial describing ischemic retinopathy, ileitis and transient monocular blindness in three out of 114 patients (2.6%). [67]

HBV and HCV infections in children are chronic infections, and are often asymptomatic but also have possible negative outcomes. Most children with chronic hepatitis B or C are expected to contribute to the pool of infected adult patients. Currently available therapeutic options for chronic hepatitis B are effective in accelerating the spontaneous course of infection in terms of anti-HBe seroconversion in children, but not in eradicating the infection. Until more therapeutic options become available, a conservative approach is generally warranted in children with chronic HBV infection. Only a minority of children with chronic hepatitis B should be evaluated for treatment. Guidelines and consensus of expert panels suggest focusing treatment on children in the immune-active phase with persistently elevated aminotransferases and evidence of active viral replication for more than 3 months. The decision to treat could be guided by the family history of liver disease, especially HCC, or by the results of liver histology that will show severe hepatitis and advanced fibrosis only in a minority of cases. So far, until more therapeutic options become available, interferon-α is the agent of choice due to the absence of risk of developing drug resistance. Currently available nucleos(t)ide analogs are secondary therapies, and their use carries a high risk of developing resistant HBV infection, limiting treatment options later in life.
On the other hand, data on the efficacy of combined treatment with pegylated interferon-α and ribavirin in children with chronic hepatitis C are encouraging. The combination therapy is more effective and better tolerated in children when compared with adults. SVR in children with genotype 1 infection is around 55%, but it is higher (>90%) in children infected by HCV genotype 2 and 3. The latter result strongly supports the treatment of children with HCV genotype 2 and 3 infection. For children infected with HCV genotype 1, given the mild natural history of the disease in childhood and the new highly effective treatment options available for adults, a conservative approach seems reasonable.

Future Perspective
In children with chronic hepatitis B, well-performed randomized controlled trials are needed to evaluate the efficacy of combined treatment of one or more antivirals with or without interferon (in the pegylated form). The results of similar studies in adults did not show a difference in sustained off-treatment virologic response and, so far, combinations are not recommended. [13,28] On the other hand, combination therapies have been proven to be more effective than monotherapy in the treatment of HIV and HCV infections, and combination therapy seems still to be a logical approach and a promising research area.
The important progress made in the development of new therapies in adults with genotype 1 infection is encouraging. Strategies in current clinical trials focus on the evaluation of different direct antiviral agents. The availability of numerous drugs belonging to different classes stimulates combination trials with multiple direct antiviral agents and with compounds targeting host cell factors aiming for interferon-free, all-oral anti-HCV therapy. [68] The possibility of both interferon-based and interferon-free regimens in combination with new specific inhibitors or direct antiviral agents active against hepatitis C seems realistic and suggests a conservative approach in children (future adults) with chronic genotype 1 infection.

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