Ribavirin In Children Research Articles

Thyroid disturbances in children treated with combined pegylated interferon-alpha and ribavirin for chronic hepatitis C.

BackgroundImmunomodulatory properties of interferon (IFN) have been documented. It may induce autoimmune diseases such as autoimmune thyroiditis with hypo- or hyperthyroidism. In addition, it may impair thyroid hormone synthesis through affecting iodide organification in thyroid gland.PurposeThe aim of this study was to describe thyroid function tests disturbances in children with chronic hepatitis C (CHC) receiving pegylated interferon-alpha (PEG IFN-α) plus ribavirin.MethodsFifty children with CHC virus infection who received combined pegylated interferon-alpha with ribavirin were selected. Other 50 apparently healthy children of matched age and sex (considered as control group) were selected. All children (100) were subject to liver function tests, virological studies, and follow-up of thyroid function test during and after the treatment course.ResultsOur study showed that 28% of children received combined PEG IFN-α plus ribavirin showed subclinical hypothyroidism. After 24 weeks treatment with combined therapy of IFN plus ribavirin, the mean level of thyroid stimulating hormone (TSH) was 3.23±88 mU/mL, while TSH was 1.16± 0.77 mU/mL before starting treatment. On the other hand, mean TSH was 1.09±0.92 mU/mL in normal control group.ConclusionThis study revealed an association between subclinical thyroid dysfunction and treatment with IFN-alpha and ribavirin in children. Further studies on larger number of patients and longer follow-up duration are recommended for further confirmation.

1037 Safety and Efficacy of Sofosbuvir Plus Ribavirin and Sofosbuvir Plus Daclatasvir With or Without Ribavirin Combinations in Children and Adolescents With Chronic Hepatitis C

INTRODUCTION: The combination of Sofosbuvir plus Ribavirin and Sofosbuvir plus Ledipasvir are recommended by American Association for the study of Liver Disease for treatment of Chronic Hepatitis C Virus (HCV) infection in adolescents; however, there is no clear recommendations for its use in children age < 12 years. The purpose of this study is to evaluate use of Sofosbuvir plus Ribavirin and Sofosbuvir plus Daclatasvir with or without Ribavirin in children and adolescents with Chronic HCV infection. METHODS: An observational (off-label), single-centre study was conducted from January 2016 to December 2018. All Chronic HCV RNA detected, aged between 3 to 17 years of either gender were included. Patients were offered one of two regimes; Sofosbuvir plus Ribavirin for 24 weeks (Regime 1) and Sofosbuvir plus Daclatasvir with or without Ribavirin for 12 weeks (Regime 2), according to their weight i.e. standard dose for patients >34kg, half of standard dose for patients weight between 17 to 34 kg and half of standard dose on alternate day for patients < 17 kg. Patients were closely monitored for any drug related adverse effects and very Rapid Virological Response (vRVR) i.e. undetectable serum HCV RNA by week 2 of treatment, then accordingly till Sustained Virological Response (SVR12) i.e. undetectable serum HCV RNA at 12 weeks after completion of treatment. RESULTS: Total 14 patients were included with mean age of 12.36 ± 5.43 years with 6 (42.9%) patients were less than 12 years and 8 (57.1%) were 12 years. Among these 9 (64.3%) were boys and 5 (35.7%) were girls. 13 (92.9%) patients were non-cirrhotic and 1 (7.1%) patient was compensated cirrhotic. 5 (35.7%) patients treated with Sofosbuvir plus Ribavirin (Regime 1) and 9 (64.7%) patients treated with Sofosbuvir plus Daclatasvir with or without Ribavirin (Regime 2). 13 (92.9%) patients achieved vRVR except 1 (7.1%) patient who achieved partial response in Regime 1. SVR12 achieved by all 14 (100%) patients. No any significant adverse effect was observed and normal growth was assessed with CDC Growth Charts. CONCLUSION: The combination of Sofosbuvir plus Daclatasvir with or without Ribavirin is not approved by the FDA or EMA for paediatric use, however, it is highly safe and effective in children and adolescents while Sofosbuvir plus Ribavirin combination showed good efficacy and comparable safety profile in age < 12 years.

Clinical observation of Huangqi injection combined with ribavirin in children with viral myocarditis

Objective To evaluate the efficacy of Huangqi injection combined with ribavirin in the treatment of viral myocarditis in children. Methods A total of 89 children with viral myocarditis were randomly divided into treatment group (45 cases) and control group (44 cases) by random number table method. The control group received ribavirin intravenously on the basis of routine treatment, and the treatment group was given Huangqi injection intravenously on the basis of the control group. Both groups were treated continuously for 14 days. The Serum creatine kinase (CK), creatine kinase MB (CK-MB), lactate dehydrogenase (LDH) and aspartate transaminase (AST) were detected by automatic biochemical analyzer. The Serum IL-6, IL-8 and TNF-α were detected by ELISA.The level of CD3+, CD4+, and the ratio of CD4+/CD8+ in peripheral blood was measured by flow cytometry, and the clinical efficacy was evaluated. Results After treatment, the level of serum CK (110.19 ± 12.17 U/L vs. 143.81 ± 17.53 U/L, t=10.530), CK-MB (18.43 ± 4.40 U/L vs. 30.28 ± 5.21 U/L, t=11.602), LDH (139.57 ± 10.36 U/L vs. 162.18 ± 13.22 U/L, t=8.992), AST (24.14 ± 2.19 U/L vs. 35.58 ± 3.34 U/L, t=19.150) in the treatment group were significantly lower than those in the control group (P<0.01). The Serum level of IL-6, IL-8 and TNF-α in the treatment group were significantly lower than those of the control group (t=14.884, 17.043 and 14.364, respectively, P<0.01). The level of CD3+, CD4+, and the ratio of CD4+/CD8+ in peripheral blood of the treatment group was significantly higher than that of the control group (t=6.256, 0.219 and 3.895, respectively, P<0.01). Conclusions The Huangqi injection combined with ribavirin can significantly reduce the degree of myocardial injury and inflammation in children with viral myocarditis, and improve the immune function of children with viral myocarditis. Key words: Myocarditis; Virus diseases; Child; Huangqi injection; Ribavirin; Immunity

Comparative effectiveness and safety of xiyanping with ribavirin for rotavirus enteritis therapy in childhood: A systematic review and meta-analysis

Purpose : To employ meta-analysis to assess the effectiveness and adverse events of Xiyanping and ribavirin in children with rotavirus enteritis. Methods : Searches included PubMed, Embase, Medline, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine Database (CBM), China Science and Technology Journal Database (VIP database), and Wanfang database from inception to March 2017. Clinical indicators, with respect to the total effectiveness rate, fever time, duration of diarrhea, creatinine kinase MB isoenzyme (CK-MB), rotavirus (RV) negative conversion rate, and adverse reaction, were compared between Xiyanping and ribavirin groups. Results : Five-hundred and twenty-six records were obtained after searching the databases, and 18 studies (3557 participants) that met the inclusion criteria were included. All of them assessed total effectiveness rate, and two records evaluated RV negative conversion rate. There were significantly higher rates in the Xiyanping group than in the ribavirin group {OR = 3.76, 95 %CI (3.03 - 4.66), p < 0.00001; OR = 2.68, 95 %CI (1.56 - 4.60), p = 0.0004}. Compared with ribavirin group, fever time, duration of diarrhea, and creatine kinase isoenzyme MB (CK-MB) were significantly lower in xiyanping group [MD = -1.23, 95 %CI (-1.64 to -0.81), p < 0.00001; MD= -2.15, 95 %CI (-2.68 to -1.62), p < 0.00001; MD = -16.90, 95 %CI (-17.23 to -16.57), p < 0.00001}. Six studies reported adverse reactions, but there was no significant difference between xiyanping and ribavirin groups {OR = 1.44, 95 %CI (0.40 - 5.17), p = 0.58}. Conclusion : This review suggests that xiyanping is more effective than ribavirin in children suffering from rotavirus enteritis. Keywords : Ribavirin, Rotavirus enteritis, Systematic review, Virazole®, Xiyanping

Kinetic of Virologic Response to Pegylated Interferon and Ribavirin in Children With Chronic Hepatitis C Predicts the Effect of Treatment.

Chronic hepatitis C is a global health problem. Although new, highly effective and safe direct-acting antivirals have been approved for adults, the only drugs currently registered for children are pegylated interferon and ribavirin. The timelines for the pediatric approval of the new treatment regimens are far off. Three phase II-III pediatric trials with direct-acting antivirals are recruiting, and the estimated dates of completion of these studies range between April 2018 and January 2023. The aim of this study was to evaluate the value of on-treatment virologic response (VR) as predictor of sustained virologic response (SVR) in a cohort of Italian children with chronic hepatitis C and to establish possible stopping rules. Sixty-four children were enrolled (January 2012 to December 2015). SVR rate was 79.7% (51/64). VR at weeks 2 to 12 were shown to be robust predictors for the attainment of SVR. The positive predictive values of VR at weeks 8 and 12 were 98% and 92.7%, respectively. The negative predictive values at the same treatment weeks were 92.9% and 100%, indicating that no child who did not achieve VR at week 12 obtained SVR and that the likelihood of achieving SVR if still positive at week 8 was very low. Our results suggest for the first time that VR at week 8 could be considered a reliable predictor of SVR. Monitoring viral kinetics is useful for predicting the success of pegylated interferon and ribavirin therapy in children.

Hepatitis C in Children Co-infected With Human Immunodeficiency Virus.

The objective of this systematic review was to summarize evidence regarding hepatitis C in hepatitis C virus/human immunodeficiency virus (HCV/HIV)-co-infected children focusing on mother-to-child transmission, clinical and laboratory features, outcome, and therapies. A literature search was performed using multiple keywords and standardized terminology in MEDLINE, EMBASE, and Cochrane databases dating back to their inception up to April 1, 2015, using the following terms hepatitis C virus, HIV, and child. Fifty-five of 367 publications were selected for inclusion. In co-infected children, HIV impacted all the different aspects of HCV infection. Maternal HIV infection increased the risk of vertical transmission of hepatitis C. Children with HCV/HIV co-infection presented a lower rate of spontaneous clearance of HCV, were more commonly HCV viraemic, and had higher values of alanine aminotransferase when compared with HCV-monoinfected children. No relevant difference was reported between monoinfection and co-infection with regard to clinical findings. Although the data on the outcome of hepatitis C in the context of co-infection were limited, they were highly suggestive of a more severe outcome in terms of fibrosis in co-infected children. No pediatric data were available on the role of antiretroviral therapy as a cofactor of liver injury in HCV/HIV co-infection. The efficacy of pegylated interferon-α and ribavirin in children with HCV/HIV co-infection was lower than in monoinfected children. The effect of HIV co-infection on HCV-related disease was clear with most studies indicating that HIV accelerates HCV progression and reduces the efficacy of the available anti-HCV therapies.

The curative effect of inhaled ribavirin in children with respiratory syncytial virus bronchiolitis

Objective To investigate the clinical effect of inhaled ribavirin on the therapeutic actions and the expression of interleukin 6(IL-6), interleukin 10(IL-10)and CysLTs in children with RSV bronchitis. Methods 81 cases of children with RSV bronchitis, were chosen and randomly divided into observing group and control group. Two groups of children were inhaled pulmicort respulas and accessed others support treatment, until the symptoms disappeared. But observing group were added with ribavirin atomization. Treatments time and symptoms disappearance time in the hospital were compared, and the serum IL-6,IL-10 and CysLTs level changes before and after treatment were observed. Results Treatments time and symptoms(wheezing, coughing, dry and wet rale)disappearance time in observation group were shorter than those of the control group with(6.58±1.36)d vs.(8.92±1.12)d,(1.21± 0.59)d vs. (2.68±1.22)d,(4.86±1.31)d vs.(7.34±1.39)d and(4.00±1.52)d vs.(6.37±1.58)d, which with significant differences(t＝-8.387,-7.012,-8.267,-6.887,all P＜0.01). Before the treatment, two groups had no significant difference(P＞0.05). After treatment, the levels of serum IL-6 and CysLTs were significantly lower in the observation group, and the levels of IL-10 were higher with(76.59±10.77)ng／L vs.(116.81±10.81)ng／L,(34.40±7.19)ng／mL vs.(48.26±8.36)ng／mL and,(43.25±3.97)ng／L vs.(31.39± 4.81)ng／L. The significant differences were observed in two groups(t＝-16.74,-8.024,12.315,all P＜0.05). Conclusion Compared with general therapy, the curative effect was significant. Combined inhaled ribavirin and pul-micort respulas in RSV bronchitis early, can reduce patients'clinical symptoms and the treatment time. Key words: Respiratory syncytial virus; Bronchiolitis; Ribavirin

Efficacy of Pegylated Interferon α‐2b and Ribavirin in Chronic Hepatitis C Virus (Genotypes 1 and 4) Infection

The course of chronic hepatitis C in children is often mild or asymptomatic, but may lead to liver cirrhosis and neoplasm. The aim of our study was retrospective evaluation of treatment efficacy using pegylated interferon (IFN)-α2b with ribavirin in children and adolescents with chronic hepatitis C, both treatment naïve and re-treated. The study comprised 79 patients with chronic hepatitis C ages 8 to 18 years (43 patients re-treated; 54 infected with genotype 1 hepatitis C virus and 25 with genotype 4), treated with pegylated IFN-α2b (1.5 μg · kg⁻¹ · week⁻¹) plus ribavirin (15 mg · kg⁻¹ · day⁻¹) for 48 weeks. The primary endpoint was sustained virologic response (SVR). Early viral response (EVR) was observed in 43.1% and end-of-treatment response in 47.9% of patients. In 44.3% of patients, SVR was achieved, which was maintained for at least the next 6 months. Patients not treated before significantly more frequently attained EVR, end-of-treatment response, and SVR (64%, 65.6%, and 63.9%, respectively) as compared with re-treated patients (30%, 33.3%, and 27.9%, respectively). Among 28 patients who attained EVR, 23 achieved SVR. In 2 patients, despite lack of EVR, SVR was observed. There were numerous adverse effects. They were not so severe as to discontinue therapy. Combined therapy with pegylated IFN-α2b and ribavirin in patients with chronic hepatitis C, infected with hepatitis C virus genotypes 1 and 4, was more effective in treatment-naïve patients (63.9%) as compared with re-therapy cases (27.9%). SVR was maintained for at least the next 6 months in all of the patients. The applied treatment has limited efficacy and evokes numerous adverse effects; thus, search for new methods of treatment is mandatory.

Commentary on: The optimal Dose of Ribavirin for Chronic Hepatitis C: From Literature Evidence to Clinical Practice

Commentary on: The optimal Dose of Ribavirin for Chronic Hepatitis C: From Literature Evidence to Clinical Practice

Pegylated interferon alfa and ribavirin for children with chronic hepatitis C

To study current treatment options for pediatric hepatitis C infection and their associated success rates. We retrospectively reviewed charts of thirty children who had been treated with combination therapy of pegylated interferon alfa plus ribavirin for chronic hepatitis C infection. Patients had been treated with ribavirin (15 mg/kg per day) and either pegylated interferon alfa 2a (180 mg/m(2) once weekly) or pegylated interferon alfa 2b (1.5 mg/kg once weekly). Patients' follow-up included subjective assessment of complaints, physical examination including weight and height, as well as laboratory evaluations for viral load [before treatment, at 12 wk, and 6 mo following treatment completion, as determined by sustained viral response (SVR)], complete blood count, liver enzymes, alkaline phosphatase, bilirubin, renal function tests, and thyroid function tests. For patients not achieving a two log decrease in viral load at treatment week 12, treatment was discontinued and the patient was considered a treatment non-responder. Thirty children aged 3-18 years were included in the study. Twenty patients (11 males, 9 females) received pegylated interferon alfa 2b and ten patients (6 males, 4 females) received pegylated interferon alfa 2a. Twenty-three patients were infected with genotype 1, six patients were infected with genotype 3, and one patient was infected with genotype 2. Twenty patients (67%) achieved SVR. Treatment success rates were 90% with pegylated interferon alfa 2a vs 55% with pegylated interferon alfa 2b. Although a trend was noted for improved outcomes in the group receiving pegylated interferon alfa 2a, there were no statistically significant outcome differences between the two treatment groups (P = 0.1). Treatment success was 56.5% for patients infected with genotype 1 virus, compared to 100% for patients infected with other genotypes (P = 0.064). There was no difference in treatment response between males and females. A cut-off age of twelve years was used to dichotomize younger vs older participants; however, no difference in treatment response was observed between these groups. Using multivariate regression analysis, we could not determine predictors for achieving SVR from among the variables we examined (age, sex, and viral genotype). Although we noted a trend toward SVR with peginterferon alfa-2a, there was no statistical difference between the two peginterferons. A high incidence of adverse reactions to treatment was noted. Twenty-five patients (83%) suffered from at least one adverse reaction, but most experienced more than one adverse reaction. All patients except one became leukopenic (white blood cell count less than 5500 leukocytes/μL), six (20%) became anemic (hemoglobin less than 110 g/L), and one (3.3%) became thrombocytopenic (platelets less than 100 000/μL). Combination therapy to treat hepatitis C in children is as effective as in adults. There may be a benefit for treatment with pegylated interferon alfa 2a.

Treatment of Chronic Hepatitis B and C in Children

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.

XVIII Latin American Congress

XVIII Latin American Congress

Sustained Viral Response and Hematological Adverse events During Chronic Hepatitis C Infection Treatment

Dear Editor, Hepatitis C virus (HCV), as a causative agent of chronic liver disease, has infected approximately 175 million people (almost 3%) of the world's population; and 3 to 4 million new cases are added to this figure annually [1]. Chronic HCV infection may progress to severe outcomes in the form of cirrhosis and hepatocellular carcinoma (HCC) [2]. Currently, there is no effective HCV vaccine on the horizon due to a lack of a susceptible small animal model, an absence of neutralizing antibodies, and a high degree of viral genomic diversity and mutagenicity; therefore, successful treatment of HCV infection is very much needed. A few years ago, the standard of care (SOC) for chronic HCV infection consisted of subcutaneous injection of conventional Interferon (IFN)-α-2, 3 times per week, plus an oral, daily dose of Ribavirin (RBV) for 24 to 48 weeks [2][3]. This therapy is not ideal because of a very low sustained virologic response [(SVR) i.e., HCV RNA undetectable 6 months after the end of treatment]. The current SOC consists of pegylated INF-α-2 once a week plus daily RBV for 24 to 72 weeks [4]. This treatment aims to achieve a high SVR [5]; however, different people respond differently to this SOC regimen depending on many factors, particularly the age, sex, and ethnicity of the patient; the duration of infection; adiposity; the degree of aminotransferase elevation; HCV genotype; pretreatment viral load; and single nucleotide polymorphisms of interleukin-28B gene [6]. Recently, oral protease inhibitors ( e.g., telaprevir or boceprevir) have been added as direct-acting antivirals to the SOC treatment as a triple therapy, particularly in patients with HCV genotype 1 [7]. We were interested in Pawlowska et al.'s study, which examined correlations between the hematological adverse events and the SVR in children undergoing therapy for chronic HCV infection [8]. Specifically, Pawlowska et al. assessed the interdependence of the SVR and the hematological characteristics (leukocyte count, platelet count, and hemoglobin levels) in patients with chronic HCV infection during treatment with IFN and RBV. They divided their sample of children into two groups: patients in Group I were treated with conventional IFN-α-2b plus RBV, and patients in Group II were treated with pegylated IFN-α-2b plus RBV. They concluded that mild decreases in hemoglobin levels, leukocyte counts, and platelet counts during treatment with IFN and RBV in children with chronic HCV infection may be factors associated with SVR induction. Hemoglobin levels decreased significantly in patients who achieved SVR compared to the nonresponders in both groups. In a similar study by Sievert et al. [9] the virologic responses were also higher in anemic patients than in patients who did not develop anemia. After 12 weeks of therapy, the leukocyte and platelet counts were significantly lower in children treated with pegylated IFN-α-2b plus RBV than in those treated with conventional IFN plus RBV [8]. The hematological toxicity that occurs during therapy can result in modifications in dosage or even, in the worst-case scenario, withdrawing INF therapy, which decreases the chances of successful therapy and increases the risk of impaired liver function with cirrhosis and HCC as potential consequences [10]. Two studies have suggested that pegylated INF therapy combined with Danazol could be used to effectively treat patients suffering from HCV-related thrombocytopenia; this combined therapy avoids temporarily reducing or definitively stopping pegylated INF treatment and increases platelet levels [10][11]. The literature has clearly established that the rate of SVR with pegylated INF and RBV is comparatively higher in patients with genotypes 2 and 3 (80%) than in patients with genotypes 1 or 4 (40-50%) [4] . Despite achieving a higher SVR rate, one of the drawbacks of pegylated INF is that it is least 25 times more expensive than conventional interferon, making it unaffordable for many poor people in developing countries [5]. Suwantarat et al. found that chronic HCV-infected patients with SVR had significantly lower white blood cell and platelet counts at the end of treatment compared to those without SVR. These findings suggest that patients who develop leucopenia or thrombocytopenia during interferon treatment respond well to the therapy, and these side effects, if not severe, may not be reasons to withhold or reduce the dose of the treatment. They hypothesized that the greater cytopenia might be an indication of greater tumor necrosis factor activity in a specific treatment recipient, which translates into a higher SVR [12].

Hematological Adverse Events and Sustained Viral Response in Children Undergoing Therapy for Chronic Hepatitis C Infection

Treatment of hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin (RBV) is associated with adverse events, which may affect the patient's adherence to the treatment regimen and the treatment efficacy. The aim of this study was to assess the sustained viral response (SVR) and interdependence between the haematological characteristics (leukocyte count, platelet count, and haemoglobin levels) in patients with chronic hepatitis C (CHC) infection during treatment with IFN and RBV. We conducted a retrospective cohort study of 170 children with CHC infection who completed treatment with IFN-α and RBV. The children were divided into 2 groups: the first group (group I, n = 119) underwent a 48-week course of treatment with recombinant IFN α-2b (Intron A) at a dosage of 3 MU 3 times a week subcutaneously and RBV at a dosage of 15 mg/kg per day orally, and the second group (group II, n = 51) was administered pegylated IFN (peg-IFN)-α-2b (PegIntron) at a dosage of 1.5 μg/kg per week subcutaneously and RBV at a dosage of 15 mg/kg per day orally for 48 weeks. The dose of IFN was not adjusted but that of ribavirin was in 2 children from group II. Hematological growth factors and erythropoietin were not used. SVR was defined as undetectable serum HCV RNA 24 weeks after the end of treatment (study week 72). Serum HCV RNA was determined by performing polymerase chain reaction, and the HCV genotypes and hematological parameters were evaluated. Serum HCV RNA levels were analysed by descriptive statistics. Means and standard deviations were calculated for values collected at the baseline, on the 12th and 48th weeks during treatment, and after 24 weeks of untreated follow-up (study week 72). Eighty-six (50%) of the 170 patients who underwent treatment achieved SVR: 62 (51%) out of 119 children from group I and 24 (47%) out of 51 from group II. The mean serum hemoglobin levels and leukocyte and platelet counts at week 12 were significantly lower than the baseline values in both responders and non-responders from both the groups (P < 0.05). In the responders in group I, the mean levels of serum hemoglobin after 24 weeks of treatment and at the end of therapy were significantly lower than the mean levels at baseline. In the group treated with peg-IFN-α-2b and RBV (group II), the mean serum hemoglobin levels at week 12 was lower in the responders than in the non-responders (P < 0.05). The decrease in the hemoglobin levels was associated with viral response. In both the responders and non-responders from both the groups, leukocyte counts decreased during treatment, and after 12 weeks, they were more significantly lower than the baseline value. The decrease was more marked in children treated with peg-IFN-α-2b + RBV (P < 0.05). After 12 weeks of treatment, the platelet count was low in children from group II who had achieved SVR. A mild decrease in hemoglobin levels and leukocyte and platelet counts during treatment with IFN and RBV in children with CHC infection may be factors responsible for SVR induction.

Hematological Adverse events and Sustained Viral Response in Children Undergoing Therapy for Chronic Hepatitis C Infection

: Background: Treatment of hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin (RBV) is associated with adverse events, which may affect the patient's adherence to the treatment regimen and the treatment efficacy.Objectives: The aim of this study was to assess the sustained viral response (SVR) and interdependence between the haematological characteristics (leukocyte count, platelet count, and haemoglobin levels) in patients with chronic hepatitis C (CHC) infection during treatment with IFN and RBV.Patients and Methods: We conducted a retrospective cohort study of 170 children with CHC infection who completed treatment with IFN-α and RBV. The children were divided into 2 groups: the first group (group I, n = 119) underwent a 48-week course of treatment with recombinant IFN α-2b (Intron A) at a dosage of 3 MU 3 times a week subcutaneously and RBV at a dosage of 15 mg/kg per day orally, and the second group (group II, n = 51) was administered pegylated IFN (peg-IFN)-α-2b (PegIntron) at a dosage of 1.5 μg/kg per week subcutaneously and RBV at a dosage of 15 mg/kg per day orally for 48 weeks. The dose of IFN was not adjusted but that of ribavirin was in 2 children from group II. Hematological growth factors and erythropoietin were not used. SVR was defined as undetectable serum HCV RNA 24 weeks after the end of treatment (study week 72). Serum HCV RNA was determined by performing polymerase chain reaction, and the HCV genotypes and hematological parameters were evaluated. Serum HCV RNA levels were analysed by descriptive statistics. Means and standard deviations were calculated for values collected at the baseline, on the 12th and 48th weeks during treatment, and after 24 weeks of untreated follow-up (study week 72).Results: Eighty-six (50%) of the 170 patients who underwent treatment achieved SVR: 62 (51%) out of 119 children from group I and 24 (47%) out of 51 from group II. The mean serum hemoglobin levels and leukocyte and platelet counts at week 12 were significantly lower than the baseline values in both responders and non-responders from both the groups (P < 0.05). In the responders in group I, the mean levels of serum hemoglobin after 24 weeks of treatment and at the end of therapy were significantly lower than the mean levels at baseline. In the group treated with peg-IFN-α-2b and RBV (group II), the mean serum hemoglobin levels at week 12 was lower in the responders than in the non-responders (P < 0.05). The decrease in the hemoglobin levels was associated with viral response. In both the responders and non-responders from both the groups, leukocyte counts decreased during treatment, and after 12 weeks, they were more significantly lower than the baseline value. The decrease was more marked in children treated with peg-IFN-α-2b + RBV (P < 0.05). After 12 weeks of treatment, the platelet count was low in children from group II who had achieved SVR.Conclusions: A mild decrease in hemoglobin levels and leukocyte and platelet counts during treatment with IFN and RBV in children with CHC infection may be factors responsible for SVR induction. Implication for health policy/practice/research/medical education:The aim of the study was to assess the dependences between the kinetics of haematological exponents (leukocytes count, platelets count,haemoglobin level) during CHC treatment with interferon and ribavirin and viral response.our data has demonstrated that mild decrease of hemoglobin levels, leukocytes and platelets counts during treatment with IFn and ribavirin of chronic hepatitis C in children may constitute the factors of achieving sustained virologic response. Thus, close monitoring of blood counts during treatment is necessary. This article is important for hepatologists and pediatric medicine doctors, who treat patients with chronic hepatitis C. Please cite this paper as:pawlowska M, pilarczyk M, Foksinska A, Smukalska e, HalotaW. Hematological Adverse events and Sustained Viral Response in Children Undergoing Therapy for Chronic Hepatitis C Infection. Hepat Mon. 2011;11(12):968-74. DoI: 10.5812/kowsar.1735143X.789

Safety and Pharmacokinetics of Ribavirin for the Treatment of La Crosse Encephalitis

La Crosse viral encephalitis (LACVE) is associated with residual epilepsy and neurocognitive deficits in survivors. This report summarizes 3 phases of clinical studies of children treated with intravenous (IV) ribavirin (RBV), each one exploring a different phase (I, IIA, IIB) of clinical trial development. In phase I, 7 children with life-threatening LACVE were treated with emergency use RBV using a moderate IV dose (8.33 mg/kg/dose q 8 hours day 1, 5 mg/kg/dose q 8 hours days 2-10). In phase IIA, 12 children with severe LACVE were enrolled: 8 treated with RBV (same dose as phase I) and 4 with placebo. In phase IIB an escalated dose was used (33 mg/kg dose 1, then 16 mg/kg/dose q 6 hours for 4 days, and 8 mg/kg/dose q 8 hours for 3 days). In a group of 15 children treated in phase I and phase IIA, RBV appeared safe at moderate dose, but based on steady-state RBV levels of 9.3 μM, estimated cerebrospinal fluid levels were less than 20% of the EC50 of RBV for LACVE. At the escalated dose used in phase IIB, adverse events occurred, likely related to RBV, and therefore the trial was discontinued. Nevertheless, valuable pharmacokinetic (PK) and safety data were obtained at moderate dose, with potential treatment implications for other indications. Although the results do not support the use of RBV for LACVE, this nevertheless is the largest study of antiviral treatment for LACVE to date and the largest pharmacokinetic analysis of IV RBV in children for any indication.

Chronic hepatitis C virus infection in children and adolescents: Epidemiology, natural history, and assessment of the safety and efficacy of combination therapy

Hepatitis C virus (HCV) is the most common cause of chronic liver disease of infectious etiology in children. Most of the children infected with HCV are asymptomatic, and only a few of them develop signs and symptoms of end-stage liver disease early in life. It is not possible to predict either in which patients HCV infection will have a bad outcome or the critical time in early adulthood when disease progression will accelerate. The experiences with therapy in children with chronic hepatitis C are based on earlier and continuing data from adult trials. The currently recommended treatment for chronic HCV infection in adults is the combination of peginterferon-á and ribavirin. The choice of this regimen is based on the results of randomized clinical trials that demonstrated the superiority of this combination treatment over standard interferon-á and ribavirin. Recently, results of pivotal, multicenter, interventional open-label studies on combined treatment with peginterferon-á and ribavirin in children have been published, and the US Food and Drug Administration and the European Medicines Agency have approved the combination therapy in those older than 3 years. The aim of this review is to evaluate critically the available data regarding the safety and efficacy of combination treatment with peginterferon-á and ribavirin in children.

Ophthalmologic Complications in Children With Chronic Hepatitis C Treated With Pegylated Interferon

Interferon treatment for chronic viral hepatitis C (HCV) has been associated with the development of retinopathy in 19% to 29% of adults. Our purpose is to describe the ophthalmologic complications of pegylated interferon-alpha2a with either placebo or ribavirin in children with chronic HCV (the PEDS-C trial). Prospective, comprehensive ophthalmologic examinations including slit lamp at enrollment and after 24 and 48 weeks of treatment of 114 children participating in a randomized clinical trial. One hundred and twenty-eight children were screened for entry, of whom 123 had an eye examination and no child had existing retinal disease. One hundred fourteen children were eligible and were treated. One hundred ten children had an eye examination at 24 weeks and 103 children at 48 weeks. Three of 114 subjects (2.6%) developed documented (n = 2) or possible (1) serious eye complications. One subject developed evidence of ischemic retinopathy (cotton-wool spots) by week 24, 1 developed uveitis by week 48, and 1 reported at week 48 transient (<4 hours) monocular blindness that had occurred at week 36 with a subsequent normal examination at week 48. Ophthalmologic complications are infrequent in children who are treated with pegylated interferon-alpha2a for HCV (2%-3%). Because of the potential severity of ischemic retinopathy and uveitis, prospective ocular assessment should remain part of the monitoring strategy for children who are treated with interferon for HCV.

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin

Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.

Mutation frequency of NS5A in patients vertically infected with HCV genotype 1 predicts sustained virological response to peginterferon alfa‐2b and ribavirin combination therapy

Viral genome analyses performed in adult HCV-patients yielded very inconsistent results and are not transferable to children who are often infected vertically during a state of high immune tolerance. We analysed the mutational frequency in the PKR-binding domain (PKR-BD) of NS5A and PePHD of E2 protein pre- and post-treatment with peginterferon-alfa-2b and ribavirin in children chronically infected with HCV genotype 1. Amino acid sequences of NS5A (2 209-2 274) and E2 (618-681) were determined in serum samples using standard PCR procedures. Concerning the PKR-BD a significant higher number of mutations was observed in vertically compared to horizontally infected patients (2.14 vs 1.24, P-value = 0.03). This difference was exclusively based on the increased number of mutations in responders vs non-responders in vertically infected patients (2.95 vs 1.33; P-value = 0.02). While all patients with at least four mutations (n = 3) did respond to therapy, no other predictive parameters could be identified. In the PePHD no differences could be observed between either of these groups. These findings support the idea that viral properties, mode and therewith time of infection in terms of immune tolerance are equally important factors for predicting SVR in children. However given the low number of cases further studies are required to confirm this hypothesis.