Although the prevalence of chronic HCV is lower in children than adults, an estimated 5 million children worldwide have active HCV infection (Gower, 2014). Data from the National Health and Nutrition Examination Survey (NHANES) indicate 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 US are HCV antibody positive (Denniston, 2014).

As birth to an HCV-infected mother is a known risk for infection, such offspring should be evaluated and tested for HCV. The rate of mother-to-child transmission (MTCT) of HCV infection is approximately 5%, although rates are higher among women with inadequately controlled HIV coinfection, and women with higher HCV-RNA levels, or viral loads (>6 log₁₀ IU/mL) (Benova, 2014); (Delotte, 2014); (Cottrell, 2013). Identifying, following, and treating exposed children is recommended. The basis for evaluation early in life is HCV-RNA testing, as maternal antibodies and consequently anti- HCV assay positivity may persist for 18 months. About 25% to 50% of infected infants spontaneously resolve HCV infection (loss of previously detectable HCV RNA) by 3 years of age (EPHCVN, 2005); (Mast, 2005).

There is considerable debate about the utility of HCV-RNA testing within the first year of life. Proponents argue that use of a highly sensitive RNA assay early in life can increase the rate of infected infants detected, and that a negative result strongly suggests the infant is not infected while a positive result helps identify HCV cases earlier. Proponents also want to seize opportunity to test in a patient group that is often lost to follow up. Opponents argue that early testing does not change the need for definitive testing at or after 18 months; HCV RNA is more expensive than an antibody-based test; and there is no intervention or treatment that will occur prior to age 3—because of lack of approved drugs for this age group and to allow for possible spontaneous clearance. One large single center study demonstrated that HCV RNA testing done in exposed infants aged 2 months to 6 months led to reliable positive and negative results that correlated with ultimate testing at 18 months (Honegger, 2018). There is no value in repeated HCV-RNA testing prior to 18 months of age, but anti- HCV testing should take place at or after 18 months of age.

HCV-infected children often face discrimination and stigmatization in school and child-care settings that is driven by inadequate public understanding of hepatitis C. HCV is not transmitted by casual contact in the absence of blood exposure. Families should not be forced to disclose a child’s HCV infection status, and children should not be restricted from any routine childhood activity.

The risk of sexual transmission of hepatitis C is considered very low/rare. Sexual transmission occurs but generally seems to be inefficient except among HIV-infected men who have unprotected sex with men (see HCV Testing and Linkage to Care) (Schmidt, 2014). Adolescents with HIV infection and those with multiple sexual partners or sexually transmitted infections (STIs) should be encouraged to use barrier precautions to prevent sexual transmission of HCV and other STIs. Other adolescents with HCV infection should be counseled that the risk of sexual transmission is low but barrier precautions are recommended for other reasons (see Testing and Linkage to Care: Table 2 - Measures to Prevent Transmission of HCV).

In children, liver disease due to chronic HCV infection generally progresses slowly, and cirrhosis and liver cancer are infrequently encountered. Although elevated serum aminotransferase levels are often noted, HCV-infected children younger than 3 years virtually never have advanced liver disease.

The initial assessment of children with chronic HCV infection includes exclusion of other causes of liver disease, assessment of disease severity, and detection of extrahepatic manifestations of HCV. Testing for concomitant HBV (HBsAg, anti-HBc, and anti-HBs), HIV (anti-HIV), and immunity to HAV (anti-HAV IgG) are recommended due to shared risk factors and the need to vaccinate all nonimmune children that may not have received routine childhood vaccines against HAV and HBV.

Disease staging in children can be accomplished via physical examination and the assessment of routine laboratory parameters including albumin, serum aminotransferase levels, total bilirubin, international normalized ratio (INR), and platelet count every 6 to 12 months. Serum fibrosis markers also hold promise to stratify disease severity but require further validation (Mack, 2012). Of note, serum aminotransferase levels are not consistently reflective of disease severity in children. In one study nearly 33% of children had normal aminotransferase levels despite substantial necroinflammation on biopsy (Casiraghi, 2004).

For children in whom advanced liver disease is a concern, liver imaging to evaluate for splenomegaly or venous collaterals is recommended initially, using liver ultrasound instead of CT or MRI due to its widespread availability and lack of ionizing radiation. Although liver biopsy is considered the gold standard regarding the grade of inflammation and stage of fibrosis, sampling artifact is problematic and most patients and practitioners prefer noninvasive alternatives, such as liver elastography, to determine the presence/absence of cirrhosis, particularly in children. Ultrasound-based liver elastography in children requires the use of specialized probes and cutoff values for advanced fibrosis/cirrhosis that differ from those used in adults, but this approach appears promising for monitoring children with chronic HCV infection (Behairy, 2016); (Geng, 2016); (Lee, 2013).

Due to the slow rate of fibrosis progression among children, there are few, if any, established bona fide risk factors for disease progression. Development of advanced liver disease in children is infrequent until more than 30 years of infection (Jhaveri, 2011); (Goodman, 2008); (Minola, 2002). However, as in adults, children with comorbid disease—such as obesity with nonalcoholic fatty liver disease and congenital heart disease with elevated right heart pressures—and those receiving hepatotoxic drugs should be monitored carefully for disease progression.

Hepatocellular carcinoma (HCC) is rarely encountered among children and has been reported almost exclusively in children with cirrhosis. There are reports that children with chronic HCV and a history of childhood leukemia may be at increased risk of developing HCC, but evidence is limited (González-Peralta, 2009). In children with cirrhosis, liver ultrasound with or without serum alpha-fetoprotein (AFP) testing every 6 months is recommended for HCC surveillance per AASLD guidelines (Bruix, 2011). A baseline endoscopy is advisable to detect esophageal varices in children with cirrhosis and every 3 years thereafter in the absence of antiviral therapy. After successful antiviral therapy, the risk for cirrhosis complications is substantially less.

In children with advanced fibrosis from chronic HCV, medications that are known to accelerate hepatic fibrosis (eg, methotrexate) should be avoided if possible. Similarly, abstinence from alcohol use is strongly advised to minimize disease progression. Although corticosteroids and other immunosuppressants may enhance HCV replication, they are not contraindicated in children with HCV and should be prescribed for appropriate indications based on overall risk vs benefit. Of note, icteric flares of HCV—as reported in children and adults with chronic HBV—have not been reported in children receiving organ transplants or cytotoxic chemotherapy. Although underlying liver disease is a risk factor for development of sinusoidal obstruction syndrome following bone marrow transplantation, the presence of HCV infection should not delay this therapy.

To remain well, untreated children with chronic hepatitis C are encouraged to maintain a healthy body weight due to the known deleterious effects of insulin resistance on fibrosis progression with HCV infection. Other commonly used medications, such as antimicrobial agents, antiepileptics, and cardiovascular agents, should be dosed per standard recommendations. However, NSAIDs and aspirin should be avoided, if possible, in children with cirrhosis and esophageal varices due to concerns of gastrointestinal bleeding and nephrotoxicity. Acetaminophen is a safe and effective analgesic for children with chronic HCV infection when dosed per package insert recommendations.

Advanced liver disease due to HCV infection is uncommon during the childhood years. However, liver disease progresses over time with increasing fibrosis severity. Although uncommon, cirrhosis is occasionally seen in infected children and adolescents younger than 18. Children have a long life expectancy during which HCV complications may develop. Infected children and adolescents may also transmit HCV to others.

Direct-acting antiviral (DAA) regimens have a very high success rate in adults with chronic HCV infection. In addition, interferon-based regimens have limited success in children with genotype 1 or 4. Interferon and ribavirin have general and pediatric-specific toxicities (eg, temporary growth impairment) that do not occur with DAA regimens. Several clinical trials are underway, early data have been published, and DAA regimens are now available for adolescents 12 years and older.

The daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) was approved for adolescents aged 12 to 17 years in April 2019. In the registration trial, 47 adolescents were treated with the adult-approved coformulated preparation; the duration of treatment was based on viral genotype, prior treatment, and cirrhosis status (Jonas, 2019).

Genotypes 1 through 4 were represented in the trial. Two participants were HIV coinfected, none had cirrhosis, and 11 had been pretreated with peginterferon/ribavirin. SVR12 was 100%. The study drugs were well tolerated with no serious adverse events and no drug discontinuations. Although there are no data from the adolescent population, EXPEDITION-8 evaluated 8 weeks of glecaprevir/pibrentasvir among 343 treatment-naive adults with genotype 1, 2, 3, 4, 5, or 6 infection and compensated cirrhosis. Overall SVR12 rates were 99.7% (334/335) in the per-protocol population and 97.7% (335/343) in the intention-to-treat population (Brown, 2019). Given the pangenotype activity, safety, and efficacy record in adult patients, glecaprevir/pibrentasvir is recommended as the first choice for adolescent treatment. As in adults, coadministration of carbamazepine, efavirenz-containing regimens, and St. John’s wort is not recommended since these compounds may decrease concentrations of glecaprevir and pibrentasvir.

The daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) is approved for use in children 12 to 17 years old. In a phase 2, multicenter, open-label study of 100 adolescents with genotype 1 treated for 12 weeks with the adult formulation of ledipasvir/sofosbuvir, SVR12 was documented in 98% of participants (Balistreri, 2017). The 2 patients who did not achieve SVR12 were lost to follow-up during or after treatment. Eighty percent of the patients were treatment naive. One patient had cirrhosis, 42 did not, and the cirrhosis status was unknown in the remaining 57. The regimen was safe and well tolerated in this population, and the adult dosage formulation resulted in pharmacokinetic characteristics similar to those observed in adults.

Treatment of children as young as 12 years is predicted to be very cost-effective with currently approved DAA regimens as well as those in clinical trials (Nguyen, 2019b). It is anticipated that additional DAA regimens will be available for children aged 3 through 11 in the near future.