Key points

Introduction

Hepatitis C virus (HCV) infection is an international health problem with an estimated prevalence of 64 to 170 million people around the world. In the United States, approximately 2.3 million people have chronic HCV infection Data from the National Health and Nutrition Examination Survey (NHANES) III for 1999 through 2002 suggest that approximately 0.17% of 6- to 11-year-olds are HCV antibody–positive (31,000) and 0.39% of 12- to 19-year olds are positive (101,000). Of the children with HCV infection, it has been reported that approximately 75% to 80% become infected chronically.

The leading source of HCV acquisition in children is perinatal transmission. The rate is thought to be about 5% from HCV viremic mothers and up to 10.8% in HCV and human immunodeficiency virus (HIV) coinfected mothers who are not receiving antiretroviral therapy.

Introduction

Hepatitis C virus (HCV) infection is an international health problem with an estimated prevalence of 64 to 170 million people around the world. In the United States, approximately 2.3 million people have chronic HCV infection Data from the National Health and Nutrition Examination Survey (NHANES) III for 1999 through 2002 suggest that approximately 0.17% of 6- to 11-year-olds are HCV antibody–positive (31,000) and 0.39% of 12- to 19-year olds are positive (101,000). Of the children with HCV infection, it has been reported that approximately 75% to 80% become infected chronically.

The leading source of HCV acquisition in children is perinatal transmission. The rate is thought to be about 5% from HCV viremic mothers and up to 10.8% in HCV and human immunodeficiency virus (HIV) coinfected mothers who are not receiving antiretroviral therapy.

Acute infection

Acute HCV infection is not commonly identified in children, unless associated with known outbreaks. Patients should be monitored for 6 to 8 weeks for spontaneous resolution before treatment is considered. However, although direct-acting antiviral therapy is recommended for the treatment of acute HCV infection in adults, these agents are not yet approved for use in children. Fulminant hepatitis C is uncommon in children, as in adults.

Natural history

Liver disease from chronic HCV infection typically progresses slowly during the childhood years. Thus, the serious complications of advanced liver disease are rare.

For children infected during infancy by vertical transmission, HCV is spontaneously cleared in 20% to 45% of cases. In a large series of 266 children with perinatally acquired HCV who were followed for a median of 4.2 years, approximately 20% cleared the infection at a median age of 15 months; 80% went on to have chronic infection. Spontaneous resolution of perinatally acquired HCV is rare after age 3. HCV infection may be acquired later in childhood, because adolescents may acquire HCV through high-risk behaviors, such as intravenous/intranasal drug use and the use of shared tattoo equipment.

Studies of HCV-infected children have demonstrated that hepatic fibrosis tends to increase with age, suggesting that the liver disease, although commonly mild, does progresses over time. Advanced liver disease is uncommon before young adulthood. However, there have been reports of decompensated cirrhosis in children as young as 4, 6, and 11 years, and cirrhosis is well-described during childhood. Factors associated with disease progression in children are immunosuppression (HIV infection or other etiologies), obesity, and likely viral factors.

Case identification

Testing all children for HCV is not recommended. In a large study of children in an urban setting, only 1 child was positive for HCV out of the 1034 children screened. A 2012 report demonstrated that the number of children identified with HCV in the United States was only a small proportion of the expected number. Only 11.7% of cases had been identified in Florida between 2000 and 2009, and nationwide, this figure was only 4.9%. In addition, in Florida, only 1.6% of the identified children were receiving care for HCV infection and 2.8% had received care within the previous 5 years. Similar findings were reported in a 2015 Australian national surveillance study looking at the incidence of childhood hepatitis C from 2003 to 2007. This study reviewed the reports of new HCV infection in children younger than 15 years reported by Australian pediatricians. There were 45 confirmed cases reported over a 5-year period. In comparison, the reports of HCV infection made through another national disease surveillance system were 6-fold higher. However, even this is an underestimation, because the Australian national incidence as predicted by statistical modeling, is 125 to 250 HCV-infected children born yearly.

Groups of children at high risk for HCV infection, for whom testing would be appropriate, are listed in Box 1 .

Diagnosis

After the first 15 to 18 months of life, the approach to diagnosis of HCV infection in children is similar to that recommended for adults. Most infected individuals are seropositive for anti HCV; infection is confirmed with polymerase chain reaction testing for HCV RNA, and HCV genotyping is recommended to help guide future treatment. In general, liver biopsy is not required typically for either diagnosis or treatment decisions in children. However, biopsy could be considered if the:

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  Degree of liver fibrosis would potentially influence treatment decisions, such as the decision to begin currently approved therapy or consider deferring treatment until new therapies are available; or

  
  
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  Patient has known or suspected other liver disease that would influence treatment decisions.

The histologic features of childhood HCV infection in children are similar to those found in adults. These include steatosis, portal lymphoid aggregates or follicles, and sinusoidal lymphocytes. The severity of fibrosis tends to be less severe in general, although cirrhosis has been reported in children.

Although serial monitoring of aminotransferases is often done in practice, it should be noted that serum aminotransferases do not always correlate with disease severity in children with HCV. In approximately one-third of children with HCV, aminotransferases are normal when there is biopsy evidence of inflammation.

Malignancy

Hepatocellular carcinoma is associated primarily with cirrhosis in HCV-infected patients. Because cirrhosis is not seen commonly in children, HCC is also rare in this population. Nonetheless, it is probably prudent to obtain liver ultrasounds and serum alpha fetoprotein annually in children with HCV-related cirrhosis.

Treatment

The goal of treatment is to reduce mortality and HCV infection-associated health problems. As in adults, the primary treatment objective is a sustained virologic response (SVR), defined as an absence of detectable viral RNA 24 weeks after the cessation of therapy.

The development of direct-acting antiviral agents and combination drug regimens are major milestones in the treatment of HCV in adults. There are currently no published studies of these direct-acting antiviral agents in HCV-infected children. Although studies of the early protease inhibitors, telaprevir and boceprevir, were initiated in the pediatric population, these were halted with the prospect of highly effective, less toxic regimens. Clinical trials using direct-acting antiviral agents without interferon in children are currently enrolling.

Because of the ongoing trials of direct-acting antiviral agents in children, treatment for chronic hepatitis C in most children should be deferred until interferon-free regimens are available to this population. Because courses of treatment are typically brief, ranging from 12 to 24 weeks, data from pediatric trials should be forthcoming within 2 years. Deferring treatment for several years is often appropriate, because most children have mild liver disease that progresses slowly. However, in the following situations, using currently approved therapy, the combination of peginterferon and ribavirin, should be considered:

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  Patient and family preference for immediate treatment.

  
  
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  Patient has another medical condition that requires prompt treatment (eg, requirement for chronic immunosuppression because of the need for organ transplant).

  
  
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  Signs of severe or progressive liver disease on liver biopsy. However, it should be noted that patients with cirrhosis do not respond as well and are at higher risk of adverse effects associated with interferon and ribavirin.

  
  
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  Patient is in a medical system in which the availability of the direct-acting antiviral drugs will be limited or unlikely.

Direct-acting antiviral agents have been approved for use in adults in the United States, Canada, the European Union, Japan, and Russia. There are reports of ongoing efforts to expand production of these medications outside North America. In addition, the pharmaceutical companies have begun licensing agreements with numerous developing countries to expand access to these medications. Whether these drugs will be available for use in children in this expanded global marketplace, and the timeframe for that availability, is uncertain at this time.