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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 6  |  Issue : 2  |  Page : 96-100

Hepatitis C virus infection in children and adolescents: A recent update


Department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Date of Submission25-Dec-2021
Date of Acceptance26-Dec-2021
Date of Web Publication28-Feb-2022

Correspondence Address:
Dr. Khan Lamia Nahid
Department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka,
Bangladesh
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pnjb.pnjb_25_21

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  Abstract 

Hepatitis C virus (HCV) infection is an emerging problem for children and adolescents. The estimated 3.5–5 million children have chronic HCV infection globally. Early detection of HCV infection and early administration of appropriate treatment in childhood are necessary to prevent decompensated liver disease and hepatocellular carcinoma as in adults. Perinatal transmission is the most common route of HCV infection in children. An antibody-based test (anti-HCV) should be done in children at or after 18 months of age to detect HCV infection. Children who are anti-HCV-positive after 18 months of age should be further confirmed with an HCV-RNA assay after age 3 to recognize chronic hepatitis C infection. These patients should be further tested to determine the genotype. Children who are anti-HCV- and HCV-RNA-positive need to be treated with direct-acting antiviral. The purpose of the article is to discuss epidemiology, natural history, diagnosis, and management of HCV infection in children and adolescents.

Keywords: Adolescents, children, direct-acting antiviral, genotype, hepatitis C infection


How to cite this article:
Nahid KL, Rukunuzzaman M, Mazumder M W, Begum F, Alam R. Hepatitis C virus infection in children and adolescents: A recent update. Paediatr Nephrol J Bangladesh 2021;6:96-100

How to cite this URL:
Nahid KL, Rukunuzzaman M, Mazumder M W, Begum F, Alam R. Hepatitis C virus infection in children and adolescents: A recent update. Paediatr Nephrol J Bangladesh [serial online] 2021 [cited 2022 May 27];6:96-100. Available from: http://www.pnjb-online.org/text.asp?2021/6/2/96/338571




  Introduction Top


Hepatitis C virus (HCV) infection is an emerging problem for children and adolescents. Early detection of HCV infection and early administration of appropriate treatment are necessary to minimize adverse health-related problems during adulthood. HCV infection constitutes major health problem in adults.[1] As children with HCV infection are mostly asymptomatic, they are suspected to be grossly underestimated.[2] If children are not detected early, they may gradually progress to decompensated liver disease and hepatocellular carcinoma as adults. Direct-acting antivirals (DAAs) can be used safely in children and can achieve sustained virologic response (SVR) as a virologic cure.[3] HCV infection in children differs from infection acquired in adulthood in various ways, including modes of transmission, rates of spontaneous clearance, or evolution of fibrosis. Perinatal transmission is the most common source of infection in children. The purpose of the article is to discuss a summary of the epidemiology, natural history, diagnosis, and management of HCV infection in children and adolescents.


  Epidemiology Top


The prevalence of chronic hepatitis C infection is lower in children than in adults. The estimated 3.5–5 million children have chronic HCV infection globally.[4],[5] Records from the National Health and Nutrition Examination Survey (NHANES) show that 0.2% of 6- to 11-year-olds (31,000 children) and 0.4% of 12- to 19-year-olds (101,000 adolescents) in the USA are HCV antibody-positive.[6] However, these reports likely underestimate the true prevalence of affected children as detection is not possible in most parts of the world.

HCV is an enveloped, single-stranded, positive sense RNA virus, and it has six genotypes with several subtypes. In adults, HCV genotype 1, subtypes 1a and 1b as well as genotype 2, subtypes 2a, 2b, and 2c are the most common types in North America. HCV genotype 3 is concentrated in South East Asia, genotype 4 in the Middle East, genotype 5 in South Africa, and genotype 6 in Asia.[7]


  Mode of Transmission Top


Perinatal transmission is the most common route of HCV infection in children, accounting for more than 1500 new cases/year in the United States.[8] The incidence of perinatal transmission is about 1–5% in HCV RNA-positive mothers, with the highest risk in mothers with high HCV viral load.[9],[10] Untreated HIV co-infection poses further risk.

Generally, HCV is spread by blood-to-blood contact associated with injection drug use, poorly sterilized medical instruments, needle stick injuries, and transfusions of blood and blood products. By means of proper blood screening, the risk from a transfusion is less than one per two million.[11]

Hepatitis C is not transmitted by casual contact, and children with HCV infection do not pose a threat to other children and can participate in any activities of school and social gathering. There should be no restrictions in regular childhood activities.[12],[13] But, education about the risk and routes of HCV transmission is necessary. Universal precautions should be maintained at school and in the home of children with HCV infection. Blood exposure should be avoided such as the sharing of toothbrushes, razors, nail clippers, etc. HCV can be detected minimally in saliva, and the risk of transmission through kissing seems to be negligible. There is no need to avoid sharing eating utensils, drinking glasses, or towels.[13]

The risk of sexual transmission of hepatitis C is very low. Sexual transmission occurs but is generally inefficient except unusual sexual practice.[14],[15],[16] Adolescents with HCV infection should be counseled about low risk of sexual transmission, but barrier precautions are recommended.

Intravenous drug abuse is a significant and increasingly common route of HCV infection in adolescents and young adults, mostly in developed countries.[17] But data are lacking for South East Asia.


  Natural History of HCV Infection Top


Liver disease caused by HCV infection in children generally progresses slowly; grave consequences such as cirrhosis or hepatocellular carcinoma are rare during childhood.

Spontaneous clearance

Infections acquired through perinatal transmission tend to clear spontaneously, with spontaneous clearance rates ranging from 20% to 45%.[18] Spontaneous clearance of HCV acquired later in life is less likely to occur.

A series of 266 children with perinatally acquired HCV were followed for a median of 4.2 years,[19] which showed that about 20% cleared the infection spontaneously, whereas 80% had chronic infection. Spontaneous clearance was less possible in children who remained polymerase chain reaction (PCR)-positive after the first year of life. Most children with chronic infection were asymptomatic, and hepatomegaly was detected in 10% in this series.

Hepatic fibrosis scores tend to increase with age, indicating that there is slowly progressive histologic injury.[20] The development of advanced disease is not common until more than 30 years after infection in children.[18] However, progression to advanced fibrosis and cirrhosis during childhood is not impossible.


  Screening of the Children Top


Universal screening for childhood HCV infection is not recommended in most communities. Screening should be done in the following children[21]:

  • Children born to HCV-infected mothers;


  • Children and adolescents with intra-familial exposure;


  • Children and adolescents emigrating from a region with a high prevalence rate of HCV infection;


  • Adolescents who have injected illicit drugs;


  • Children and adolescents with unexplained abnormal aminotransferase levels;


  • Adolescents after a needle stick injury or mucosal exposure to HCV-positive blood.



  •   When and in Whom to Start HCV Therapy Top


    All children born to HCV-infected mother should be tested for HCV infection. Testing is suggested using an antibody-based test (anti-HCV) at or after 18 months of age. Anti-HCV test in younger infants may reflect passive transfer of maternal antibody.[10] Testing of HCV-RNA assay can be measured as early as 2 months of age. Children who are anti-HCV-positive after 18 months of age should be further confirmed with an HCV-RNA assay after age 3 to recognize chronic hepatitis C infection.[22] If HCV-RNA assay is detected, the diagnosis of HCV infection is established. These patients should be further tested to determine the genotype and then monitored for disease advancement or spontaneous clearance. The genotype determination is necessary to know the duration of DAA treatment, especially if there is advanced liver disease or if previous treatment has failed.[23] DAA regimens are used for children aged 3 to <18 years with genotype 1, 4, 5, or 6 infection and for children aged 6 to <18 years with any genotype.

    Children who are anti-HCV and HCV-RNA-positive needed to be treated with DAAs. DAA treatment is recommended for all children and adolescents with HCV infection aged ≥3 years as they will get benefit from antiviral therapy, regardless of disease severity. Treatment should be postponed until at least the child’s third birthday.[24] Delaying treatment for 3 years or more is possible because a percentage of cases will resolve spontaneously by age 3 years, and the DAA regimens are not recommended in children younger than 3 years of age. The purpose of the treatment is to halt the progression of the disease and to prevent the transmission to others. Siblings of children with vertically transmitted chronic HCV should be tested for anti-HCV, if born from the same mother.


      Further Evaluation of the HCV-Confirmed Children Top


    The patient should be monitored for disease progression by:

    Serum aminotransferases: Serial measurements of serum aminotransferases should be used to monitor disease activity. Serum aminotransferase levels do not indicate disease severity.

    HCV-RNA

    The HCV-RNA assay should be done before starting treatment and 12 weeks after completion of the treatment.[9] Serial HCV-RNA testing is not necessary because it does not correlate with disease severity and does not influence the timing of treatment decisions.

    Liver biopsy

    A liver biopsy is not required to confirm the diagnosis of HCV infection. It does not affect treatment decisions. Liver biopsy is applicable for suspected advanced liver disease. Characteristic findings are portal lymphoid aggregates or follicles, sinusoidal lymphocytes, and steatosis.[25],[26]

    Monitoring children for the development of hepatocellular carcinoma is recommended for children with cirrhosis. Monitoring with liver ultrasonography and serum alpha-fetoprotein levels every 6 months is recommended.[9] Successful treatment of HCV in cirrhotic patients does not completely eliminate the risk of hepatocellular carcinoma, so monitoring these patients should be continued.[27],[28]

    Testing for co-infection

    Assessment of the patient’s HBV status is necessary before starting treatment with DAA, because latent HBV infection may be activated when HCV is treated with certain DAA regimens. HBV screening is performed by assessing hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody.[29] HCV-confirmed children should be screened for hepatitis A virus (HAV) antibodies and immunized if not immune.


      Drugs Available for Children Top


    The treatment of chronic HCV infection has improved dramatically since the introduction of DAAs and combination drug regimens.[30],[31],[32] DAA regimens are effective and well-tolerated. It can be administered orally. Previously, interferon is used which has major side effects and is not well tolerated. Regimen selection may vary by age, genotype, presence of cirrhosis, and treatment history.


      Drug Therapy for Children and Adolescents, Without Cirrhosis or With Compensated Cirrhosis (Child–Pugh A) Top


    Treatment-naive or interferon-experienced children

  • Combination of ledipasvir/sofosbuvir for children aged ≥3 years with genotypes 1, 4, 5, or 6 for 12 weeks [Table 1].


  • Combination of sofosbuvir/velpatasvir for children aged ≥6 years or weighing ≥17 kg with any genotype for 12 weeks [Table 2].


  • Combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for adolescents aged ≥12 years or weighing ≥45 kg with any genotype for 8 weeks.
  • Table 1: Weight-based dosing of ledipasvir/sofosbuvir for children aged ≥3 years

    Click here to view
    Table 2: Weight-based dosing of sofosbuvir/velpatasvir for children aged ≥6 years or weighing ≥17 kg

    Click here to view


    DAA experienced

    Genotype 1

    Combination of ledipasvir/sofosbuvir (weight-based dosing; see [Table 1]) for children and adolescents aged ≥3 years with prior exposure to an interferon (± ribavirin) plus an HCV protease inhibitor regimen without cirrhosis for 12 weeks.

    Genotype 1

    Combination of ledipasvir/sofosbuvir (weight-based dosing; see [Table 1]) for children and adolescents aged ≥3 years with prior exposure to an interferon (± ribavirin) plus an HCV protease inhibitor regimen, with compensated cirrhosis for 24 weeks.

    Genotypes 4, 5, or 6

    Combination of ledipasvir/sofosbuvir (weight-based dosing; see [Table 1]) for children and adolescents aged ≥3 years with prior exposure to an interferon (± ribavirin) plus an HCV protease inhibitor regimen, without cirrhosis or with compensated cirrhosis for 12 weeks.

    Genotypes 1, 2, 4, 5, or 6

    Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for adolescents aged ≥12 years or weighing ≥45 kg with prior exposure to an interferon-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, without cirrhosis for 8 weeks.

    Genotypes 1, 2, 4, 5, or 6

    Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for adolescents aged ≥12 years or weighing ≥45 kg with prior exposure to an interferon-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, with compensated cirrhosis for 12 weeks.

    Genotype 3

    Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for adolescents aged ≥12 years or weighing ≥45 kg with prior exposure to an interferon-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, without cirrhosis or with compensated cirrhosis for 16 weeks.

    Genotype 1

    Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for adolescents aged ≥12 years or weighing ≥45 kg with prior exposure to NS3/4A protease inhibitors but no NS5A inhibitor exposure, without cirrhosis or with compensated cirrhosis for 12 weeks.

    Genotype 1

    Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for adolescents aged ≥12 years or weighing ≥45 kg with prior exposure to an NS5A inhibitor but no NS3/4A protease inhibitor exposure, without cirrhosis or with compensated cirrhosis for 16 weeks.

    Sofosbuvir plus ribavirin

    This combination of drugs is used for treatment-naive or interferon-experienced (± ribavirin) children aged ≥3 years with genotype 2 or 3, without cirrhosis or with compensated cirrhosis (Child–Pugh A). A 12-week course is recommended for patients with genotype 2; 24 weeks is recommended for those with genotype 3.[33],[34]

    DAAs are not recommended in decompensated cirrhosis


      Follow-up After Antiviral Therapy Top


    SVR is achieved by successful hepatitis C treatment, which means virologic cure. Virologic cure should be assessed by checking the viral load at 12 weeks after completing therapy.[35] Patients with histologic evidence of fibrosis or cirrhosis require ongoing monitoring for hepatocellular carcinoma.


      Advantage of Treatment to Reduce Transmission Top


    Children who have successfully achieved SVR (virologic cure) will not transmit the virus to others. Effective treatment of HCV infection benefits public health worldwide.


      Monitoring of the Patient Top


    Routine liver function tests at initial diagnosis and at least annually thereafter are recommended to evaluate for disease progression. Vaccinations against hepatitis B virus and/or HAV are recommended for children with chronic HCV infection to prevent these infections.

    Hepatotoxic drugs should be used after assessment of potential risks versus benefits of treatment. Use of corticosteroids and cytotoxic drugs is not contraindicated in children with chronic HCV infection. Children with chronic hepatitis C are advised to maintain a healthy body weight due to the known harmful effects of insulin resistance on fibrosis progression with HCV infection.[36],[37],[38] Acetaminophen in recommended doses is not contraindicated for children with HCV infection. But the treatment period with acetaminophen should be brief as much as possible.


      Conclusion Top


    Hepatitis C infection rarely causes hepatocellular disease during childhood. But early identification of hepatitis C infection in children is necessary. If treatment is not given to infected children, it gradually progresses to end-stage liver disease during adulthood. Generally, risk of development of liver-related disease during adulthood is increased, if hepatitis C infection is not properly addressed. So early recognition of hepatitis C infection and early treatment with DAAs have utmost importance to reduce burden of the disease later in life. Although DAA regimens are generally costly, they are considered cost-effective because they can reduce disease burden during adulthood. This regimen is effective, easily administered, and require shorter duration. So, children can tolerate these oral drugs easily. More epidemiological studies are needed to know the natural history of the disease acquired perinatally or acquired during childhood and adolescence. The effect of using DAA during childhood should also be studied. In conclusion, pediatricians should be aware of natural history of hepatitis C infection, investigations, and treatment protocol in case of children and adolescents.

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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      In this article
    Abstract
    Introduction
    Epidemiology
    Mode of Transmission
    Natural History ...
    Screening of the...
    When and in Whom...
    Further Evaluati...
    Drugs Available ...
    Drug Therapy for...
    Follow-up After ...
    Advantage of Tre...
    Monitoring of th...
    Conclusion
    References
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