Hepatitis C virus infection and interferon therapy in patients with Down syndrome.

BACKGROUND: The clinical features of hepatitis C virus (HCV)-associated liver diseases, or the efficacy of interferon (IFN) therapy in children with Down syndrome (DS) remain to be elucidated. The purpose of the present paper was to survey the features of liver diseases in this subset of children and evaluate the efficacy of IFN treatment in those patients. METHODS: A questionnaire was sent to 41 members of the Japan Society of Pediatric Hepatology. Ten of them reported on 11 patients with DS who had concomitant chronic HCV infection, providing information on liver disease and the response to IFN treatment. RESULTS: Interferon therapy of 24 weeks duration using natural IFN-alpha was instituted in six of the 11 patients with DS, but none of the six patients cleared HCV-RNA from their serum. Among 12 age- and sex-matched control children who were treated with IFN using the same regimen against chronic HCV infection, half of them had a favorable response to IFN therapy with a sustained clearance of HCV-RNA from their serum. The major baseline features including alanine aminotransferase levels, HCV genotype and viral load were not apparently different between the six patients with DS and the 12 controls. CONCLUSIONS: IFN therapy for HCV infection in patients with DS may be unfavorable as compared with non-DS children.     

Increased risk of chronic hepatitis in children with cancer

BACKGROUND: There is a risk of viral hepatitis for children with cancer. Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in countries with high prevalence cause major problems in the management of cancer patients. In this study, we evaluated the incidence and chronicity of HBV and HCV infections in children with malignant diseases receiving chemotherapy. PROCEDURE: One hundred ninety-eight children with cancer (mean age = 7.5 +/- 2.5 years) and 100 healthy children as a control group were screened for HBV and HCV. Liver function tests, the number of transfusions, HBV and HCV serology were regularly monitored. In seropositive children, HBV-DNA and HCV-RNA were measured. Chronic hepatitis was defined as having an alanine aminotransferase (ALT) level three times of upper normal limit, positive HBV and HCV antigenemia for longer than 6 months. Liver biopsies were performed in all children with chronic hepatitis. The relationship between the chronic hepatitis and study parameters was statistically analyzed. RESULTS: HBsAg positivity, anti-HCV, and mixed (HBV and HCV) infection were found in 11.6, 5.5, 2% of children, respectively. Most HBV infected children developed chronic hepatitis (48%) while 26 and 21.7% became carriers and immune, respectively. One died of acute fulminant HBV hepatitis. Of HCV infected children, 63.6% also had positive HCV-RNA. Four children with mixed infection (100%) all progressed to chronic hepatitis. In this setting, chronic hepatitis was observed in 22 of 38 infected children (57.8%). The majority had leukemia and lymphoma. Children with HBsAg antigenemia developed chronic hepatitis in shorter time than HCV positive children (median 13 months vs. 51 months, P < 0.001). CONCLUSION: We observed an increased incidence of chronic hepatitis and even mortality due to HBV infection. This suggests that HBV and HCV infections are serious causes of morbidity and mortality in children with cancer.     

Post-transfusion chronic hepatitis C in children

Two hundred and twenty-six patients who received blood products for open-heart surgery in childhood were screened by a second-generation enzyme-linked immunosorbent assay and with surrogate markers for hepatitis C virus (HCV) infection, such as alanine aminotransferase (ALT). Twenty-two (14%) of the 161 recipients who received blood products before 1989 and none of the subjects who had received blood products after 1990 (the year that the blood bank began to screen for HCV antibody) were HCV seropositive. Virologic and histologic studies showed that 10 (45%) of 24 seropositive patients had persistent hepatitis C virus infection, many with ongoing hepatitis. The remaining 12 seropositive patients with absent HCV RNA had normal ALT levels, indicating resolved hepatitis C infection. Enrolment in screening is important to detect chronic hepatitis C in children who received blood products prior to screening of blood donors for HCV antibody.     

Erythema annulare centrifugum with autoimmune hepatitis

Erythema annulare centrifugum (EAC) is a rare disease entity characterized by dense perivascular lymphocytic infiltrates in dermis. It has been associated with a few conditions, though its etiology is largely unknown. To our knowledge there has been no reported association with autoimmune hepatitis described earlier. This child also was positive for hepatitis C virus antibodies, though HCV RNA was negative. We should keep in mind the false positivity of hepatitis C antibodies before deciding on its therapy     

Efficacy and safety of peginterferon-alpha2b and ribavirin combination therapy in children with chronic hepatitis C infection

BACKGROUND: Interferon (IFN)-alpha2b plus ribavirin is approved for treatment of hepatitis C in children; however, little is known about efficacy and tolerability of pegylated IFN (PEG-IFN)-alpha2b in this population. The objective of this study was to test the efficacy and safety of PEG-IFN-alpha2b plus ribavirin in children with chronic hepatitis C. METHODS: Thirty children 3-16 years of age who had detectable hepatitis C virus (HCV) RNA for >or=3 years after exposure and elevated alanine aminotransferase values received PEG-IFN-alpha2b 1.0 microg/kg/wk plus ribavirin 15 mg/kg/d for 24 weeks (genotype 2/3) or 48 weeks (genotype 1/4). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) at week 24 of follow-up. RESULTS: SVR was achieved in 50% of patients (3/3 genotype 3; 12/27 genotype 1/4). At week 12, 52% of patients were HCV RNA negative and 72% had a >2 log10 decrease in viral load, compared with baseline; 87% and 71% of these patients, respectively, attained an SVR. Therapy was discontinued in 3 patients as a result of adverse events. No patient required ribavirin dose reduction; PEG-IFN-alpha2b dose was reduced in 23% of patients to manage neutropenia. CONCLUSIONS: Combination therapy with PEG-IFN-alpha2b and ribavirin treatment was effective in children with chronic hepatitis C. Virologic status at week 12 identified future responders and nonresponders. PEG-IFN-alpha2b and ribavirin were reasonably well tolerated, with no unexpected or permanent adverse effects. Further studies are needed to identify the optimum treatment regimen for this patient population.     

The effect of early treatment in children with chronic hepatitis

BACKGROUND: The aim of this study was to compare the efficacy of interferon alpha (IFN) or IFN and ribavirin (IFN+RIB) combination therapy in children with chronic hepatitis C (CHC). Most children were infected during treatment for pediatric malignancies. PATIENTS AND METHODS: We reviewed the charts of 20 patients (11 boys and 9 girls) aged 10.6 +/- 3.7 years with CHC who were treated between 1995 and 2001. Seven patients diagnosed with CHC before 1998 were treated with 3 million units of IFN three times weekly for 6 to 12 months. Thirteen children diagnosed after 1998 were treated with 3 million units of IFN three times weekly plus 15 mg/kg of ribavirin daily for 6 months (IFN+RIB). RESULTS: Demographic and clinical characteristics were not different between the two treatment groups. A sustained complete response defined as serum alanine aminotransferase normalization and hepatitis C virus RNA clearance at 6 and 12 months after termination of treatment occurred in three of seven children (43%) treated with IFN monotherapy compared with 7 of 12 children (54%) in the group treated with IFN+RIB combination therapy (not significant). The only difference between responders and nonresponders was the duration of infection before the initiation of therapy, which was significantly shorter in responders (1 +/- 0.3 vs. 5.6 +/- 2.2; P = 0.001). CONCLUSIONS: In this small cohort of children with CHC, early initiation of antiviral treatment was associated with a sustained response rate independent of treatment type. Regular follow-up of children at risk of acquiring hepatitis C virus infection should assist in the early diagnosis. Early initiation of antiviral treatment may improve the rate of sustained response.     

Efficacy of interferons in treating children with chronic hepatitis C

Twenty-two children with chronic hepatitis serologically positive for hepatitis C virus (HCV) were treated with interferon-α (IFN-α). Liver biopsy showed chronic active hepatitis in 13 and chronic persistent hepatitis in 9 patients. A sustained clearance of HCV was observed in 8/22 children 12 months after the administration of IFN-α for 26 weeks, associated with normalization of HCV core antibody. Of these eight patients six had HCV genotype III and two HCV genotype II or IV. Hepatitis relapsed in seven other patients after completion of IFN-α with an increase in HCV core antibody titre, five with HCV genotype II, and two with HCV genotype III or IV. A second course of IFN-α suppressed the reactivation of HCV in all seven patients. Three of seven responders who relapsed after the first course remained negative for HCV RNA 12 months after their second course of IFN-α. However, the remaining four patients with HCV genotype II again relapsed after completing their second course of IFN-α. Seven children with the HCV genotype II resistant to IFN, including 8 weeks of IFN-β administration, and showed no significant reduction in HCV core antibody titre. Conclusion The genotype of HCV (III) and a reduction in the core antibody titre appear to be useful parameters for predicting the response to IFN-α therapy. Received: 12 September 1996 and in revised form: 28 January 1997 / Accepted: 11 February 1997     

Treatment of chronic hepatitis C in children

Since the discovery of hepatitis C virus (HCV) in 1989, significant advances have been made in our understanding of this important viral pathogen. Children at risk for HCV infection include recipients of potentially contaminated blood products and organ transplants, and infants born to HCV-infected mothers. Chronic HCV infection is usually asymptomatic in children but active hepatitis, cirrhosis and hepatocellular carcinoma can occur. The development of treatment strategies for chronic hepatitis C in children has directly evolved from clinical trials in adults. Sustained virologic response, defined by undetectable HCV RNA in serum 24 wk after completion of treatment, occurs in approximately 36% of children treated with conventional interferon alone and in about 50% of those given conventional interferon in combination with ribavirin. Pegylated interferon-based treatment regimens are better than those based on conventional interferon in adults but little is known about pegylated interferon in children. Factors associated with a favorable response to antiviral therapy in children are similar to those in adults and include infection with HCV genotype 2 or 3 and low pretreatment serum HCV RNA levels. Treatment related adverse events in children include 'flu-like' syndrome, fatigue, anorexia, weight loss, depression, anemia, leukopenia and thrombocytopenia.     

Decline in hepatitis B infection in sickle cell anaemia and beta thalassaemia major

Seventy five Saudi children, 55 with sickle cell anaemia and 20 with beta thalassaemia major, who were negative for all hepatitis B virus (HBV) markers five years ago were recently investigated for exposure to HBV and hepatitis C virus (HCV) infection. Of the 55 patients with sickle cell anaemia and 20 with beta thalassaemia major, 20 and five patients respectively had been vaccinated against HBV earlier and all of them still had protective antibody (anti-HBs 42-96 IU) 3-5 years after vaccination and there was no vaccine failure. Among the non-vaccinated children the exposure rates to HBV were 14.3% among those with sickle cell anaemia and 26.7% among those with beta thalassaemia and this was not statistically significant when compared with the exposure rate to HBV among the general paediatric population (20.1%). Anti-HCV positivity among those with beta thalassaemia major and sickle cell anaemia was 70% and 18.2%, respectively, and this was significantly higher than anti-HCV positivity among the control group (0.8%). Anti-HCV positivity was directly related to the amount of blood transfused and to the duration of transfusion. The results of the study show that although the exposure rates to HBV among patients with sickle cell anaemia and beta thalassaemia major were not significantly different than that among the general paediatric population, infection with HBV still takes place among non-vaccinated patients despite strict precautionary measures taken. Hence early vaccination against HBV would probably be the only effective way of controlling HBV infection. For HCV infection, and because a vaccine against HCV is still not available, preventive measures such as blood screening for anti-HCV before transfusion and stringent infection control measures are crucial steps to be implemented for the control of spread of HCV among these groups of patients.     

Decline in hepatitis B infection in sickle cell anaemia and beta thalassaemia major.

Seventy five Saudi children, 55 with sickle cell anaemia and 20 with beta thalassaemia major, who were negative for all hepatitis B virus (HBV) markers five years ago were recently investigated for exposure to HBV and hepatitis C virus (HCV) infection. Of the 55 patients with sickle cell anaemia and 20 with beta thalassaemia major, 20 and five patients respectively had been vaccinated against HBV earlier and all of them still had protective antibody (anti-HBs 42-96 IU) 3-5 years after vaccination and there was no vaccine failure. Among the non-vaccinated children the exposure rates to HBV were 14.3% among those with sickle cell anaemia and 26.7% among those with beta thalassaemia and this was not statistically significant when compared with the exposure rate to HBV among the general paediatric population (20.1%). Anti-HCV positivity among those with beta thalassaemia major and sickle cell anaemia was 70% and 18.2%, respectively, and this was significantly higher than anti-HCV positivity among the control group (0.8%). Anti-HCV positivity was directly related to the amount of blood transfused and to the duration of transfusion. The results of the study show that although the exposure rates to HBV among patients with sickle cell anaemia and beta thalassaemia major were not significantly different than that among the general paediatric population, infection with HBV still takes place among non-vaccinated patients despite strict precautionary measures taken. Hence early vaccination against HBV would probably be the only effective way of controlling HBV infection. For HCV infection, and because a vaccine against HCV is still not available, preventive measures such as blood screening for anti-HCV before transfusion and stringent infection control measures are crucial steps to be implemented for the control of spread of HCV among these groups of patients.     

An updated follow‐up of chronic hepatitis C after three decades of observation in pediatric patients cured of malignancy

Background

The aim of the study was to evaluate the clinical characteristics and the long‐term outcome of chronic hepatitis C in a cohort of Caucasian children cured of pediatric malignancy.

Procedure

The study population included 83 consecutive patients, referred to our Center with a diagnosis of leukemia/lymphoma (50) or solid tumors (33) between 1977 and 1989 and infected with hepatitis C virus (HCV) during chemotherapy.

Results

At enrollment 77 subjects were HCV‐RNA positive. After a median follow‐up of 21 years (range 13–36), a sustained virological response (SVR) was obtained in 3 of 29 patients (10%) treated with interferon (IFN), in 1 of 3 patients (33%) treated with IFN and ribavirin, and in 5 of 11 patients (42%) treated with pegylated‐IFN and ribavirin (P = 0.03). Forty‐two patients remained untreated and only one (2.5%) cleared viremia. Four of 77 patients (5%) developed cirrhosis while other 4 patients died of causes not related to liver. At last follow‐up, 72% of HCV‐RNA positive patients had abnormal ALT.

Conclusions

In patients cured of pediatric malignancy chronic hepatitis C tends to run an indolent course during childhood and adolescence but more than 70% of treated and more than 80% of untreated cases children maintained HCV viremia. Moreover, after 2–3 decades of observation, 60% of HCV‐RNA positive patients had abnormal ALT and 5% had developed cirrhosis. Among treated patients, IFN or pegylated‐IFN and ribavirin obtained the higher rate of HCV‐RNA clearance. Pediatr Blood Cancer 2010;55:108–112. © 2010 Wiley‐Liss, Inc.     

Hepatic dysfunction in children with acute lymphoblastic leukemia in remission: relation to hepatitis infection

BACKGROUND: Viral hepatitis is a cause of hepatic dysfunction in children with ALL in remission during maintenance therapy is debated. The aims of the current study were (1) to explore the incidence of hepatic dysfunction in a group of children (Egyptian and Saudi) with ALL under maintenance therapy, (2) to study the prevalence of hepatitis B (HBV) and/or C (HCV) infection and their contributions to chronic liver disease that might be induced by maintenance therapy. PROCEDURE: The current study included 105 children with ALL (54 Egyptian and 51 Saudi). All eligible patients had been on maintenance therapy for at least 12 months and all had serial assessments of liver function. These included determination of total bilirubin, AST, ALT, and alkaline phosphatase. Markers for HBV and HCV including HBsAg, anti-HBC, and anti-HCV and for some patients HCV RNA by PCR were studied. Percutaneous liver biopsy was performed for a group of children. RESULTS: The prevalence of hepatitis infection (HBV and/or HCV) among Egyptian children was found to be high (43/54-80%). Only five Saudi children had evidence of exposure to HBV (5/51-9.8%), P<0.0001. During the period of study, 22 Egyptian patients vs. four Saudi patients (41 vs. 7.8%, P<0.0001) experienced at least one episode of elevation of liver enzymes, three times the upper limit of normal or more. Twenty-six of the 48 patients (54%) with HBV and/or HCV infection had episodes of elevated liver enzymes, while there was no occurrence among the patients negative for HBV and HCV. In patients with HBV infection, the presence of HBsAg was strongly associated (100%) with elevated liver enzymes. Histopathologic examination of liver biopsies obtained from 35 patients revealed that all five patients negative for HBV and HCV had normal liver biopsies in spite of being under maintenance therapy. CONCLUSION: In children undergoing treatment for ALL, elevations in liver enzymes may be primarily due to hepatitis viruses. However, maintenance therapy using known hepatotoxic drugs, may have additive deleterious effects. Liver enzymes are normalized in affected patients when maintenance therapy is temporarily suspended.     

Management of chronic hepatitis B and C virus infections

Hepatitis B and C virus (HBV and HCV) infections present an important health problem causing significant morbidity and mortality on a worldwide scale. The younger the subjects infected, the higher the risk predisposing to progression towards chronic infection. Treatment of chronic HBV and HCV infections is aimed at reducing hepatic inflammation and thus improving the symptoms, decreasing the likelihood of long-term sequelae such as hepatocellular carcinoma, and increasing the survival rate. Interferon accelerates the spontaneous course of chronic HBV infection in children with greater disease activity and lower levels of replication. There is limited information on the use of lamivudine and its long-term benefit in children with chronic HBV infection. The response of combination therapy with IFN and ribavirin in children with chronic HCV infection is still under investigation. The long-term clinical and virological effects of various drugs used in chronic HBV and HCV infections on children remain to be evaluated.     

Relation between serum hepatitis C virus-RNA levels and efficacy of interferon-β therapy

We performed two courses of interferon-β (IFN-β) to a child with chronic hepatitis C. A complete response was not obtained by the first interferon treatment, however, the results of the second treatment differed from those of the first. Hepatitis C virus (HCV)-RNA remained negative and both aspartate aminotransferase and alanine aminotransferase levels remained normal after completion of the second course. From these results we estimated that HCV-RNA levels before IFN therapy could be significantly associated with the efficacy of this treatment. The serum level of HCV-RNA was 10⁶ copies/50 μL before the first treatment, but was 10³ copies/50 μL before the second course. We conclude that IFN therapy to children with hepatitis C should always be directed at providing a cure. Even if the clinical effects of the first course are minimal decreasing quantities of HCV-RNA still offer hope for cure by subsequent readministration.     

Liver transplantation in a child with multifocal hepatocellular carcinoma hepatitis C and management of post‐transplant viral recurrence using boceprevir

HCV infection is the leading cause of liver transplantation in the adult population in the United States. HCV infection occurs in 0.2–0.4% of the pediatric population and progression to HCC is uncommon. Liver transplantation for HCV in children is rare. In this report, we present a case of pediatric patient with HCV and multifocal HCC at the age of 13 who underwent successful liver transplantation. While good graft function was initially observed, at one month after transplant, he experienced significant hepatitis C recurrence. He was treated with low‐accelerating dose regimen antiviral therapy of PEG‐IFN and RBV, followed by addition of a protease inhibitor, boceprevir, which led to viral clearance. To our knowledge, this is the first case report describing the post‐transplant course of a child transplanted for HCV and HCC, and the first pediatric case report on using the triple therapy for management of post‐liver transplant recurrence of HCV. This case report demonstrates the need for increased vigilance of surveillance for HCC during childhood.     

Interferon therapy for Japanese hemophiliacs with chronic hepatitis C

Eight Japanese hemophiliacs with chronic hepatitis C (CHC) received interferon (IFN) therapy and four of them (50%) responded completely. Non-responders included 3 double-infected patients: I with hepatitis B virus (HBV) and 2 with human immunodeficiency virus-1 (HIV-1). In one of the patients with HIV-1 double infection, the absolute number of CD4* lymphocytes decreased during IFN therapy. These findings suggest that hemophiliac patients with CHC can respond well to IFN therapy, but in patients who are double-infected with HBV and HIV-1, the indication of IFN therapy should be considered seriously.     

Chronic non-A, non-B hepatitis: role of hepatitis C virus.

Thirty three consecutive children with chronic non-A, non-B hepatitis (NANBH) were studied during a four year period to evaluate clinical and histological features and the role of hepatitis C virus (HCV). All patients were asymptomatic. Thirteen (39%) of them were anti-HCV positive. A history of parenteral exposure was significantly more frequent among anti-HCV positive (69%) than anti-HCV negative patients (15%). Aminotransferase serum values were not statistically different between anti-HCV positive and anti-HCV negative patients. Unlike adults, cirrhosis was never found in the children studied. Our results suggest that chronic NANBH is, during childhood, an asymptomatic disease and that the prevalence of HCV infection is lower than in adults. As the majority of the children with chronic NANBH showed no evidence of HCV infection, it seems unwarranted to identify NANBH with HCV infection in children. The lack of cirrhosis in paediatric patients is probably related to a shorter duration of liver disease.     

静注免疫球蛋白对输血后丙型肝炎病毒感染的预防作用

目的了解静注免疫球蛋白（IVIG）对输血后丙型肝炎病毒（HCV）感染的预防作用。方法68例血液病患儿分为2组，IVIG组38例，均输往有IVIG和其他血液成分;对照组30例，单纯输血者。HCV-Ab采用酶联免疫法，HCV-RNA采用PCR法。结果IVIG组部分病例出现被动输入的HCV-Ah，HCV-RNA阴性，无HCV感染病例;对照组2例发生HCV感染，HCV-Ab和HCV-RNA阳性。结论本研究结果提示IVIG可能有预防输血后HCV感染的作用。     

Chronic viral hepatitis

Among hepatitis A to E viruses, hepatitis B, C, and D viruses can cause chronic hepatitis, in both children and adults. Hepatitis B virus (HBV) infection is the most prevalent and important one. Perinatal transmission accounts for about 40–45% of chronic HBV infection in hyperendemic areas. Horizontal transmission through intramuscular injection using non-sterile needles and intrafamilial spread accounts for the other half of carriers. During the natural course of HBV infection, the host gradually clears HBV and hepatitis B e antigen (HBeAg), liver damage and elevation of aminotransferases occur during the process of HBV clearance. The most effective way to eliminate HBV infection is immunoprophylaxis starting since birth. It can prevent both HBV and hepatitis D virus (HDV) infections. Hepatitis C virus (HCV) infection in children occurs mainly in high risk children, such as those who received blood product or injection using non-sterile needles, or infants of HCV viremic mothers, etc. Screening of blood product reduced markedly the prevalence of post-transfusion HCV infection, but the prevention of sporadic cases requires HCV vaccination which is still under investigation.