Pediatric Hepatitis C

Several distinct genotypes of hepatitis C virus have been identified, and genotyping has proven to be a useful clinical tool because the response to therapy and prognosis is influenced by the viral genotype. Genotype 1 is less than half as likely as other genotypes to respond to therapy, and the combination therapy regimens vary depending on the different genotypes (see Medication).

Unfortunately, most patients have chronic infection and are at risk for progressive liver disease. Furthermore, diagnosis primarily relies on identifying the risk factors of transmission because infected individuals typically have few or no symptoms. Once hepatitis C virus infection is diagnosed, current treatment options for eradication are limited and often result in significant adverse effects (see Treatment).

Although hepatitis C virus infection is uncommon in the pediatric population, the caregiver should be familiar with the basic concepts. For example, patients transfused as recently as July 1992 may have been exposed to the virus. Clinicians may also need to be aware of how to counsel parents of children exposed to HCV in utero. Even though most of these children will remain uninfected or clear their infection, considerable anxiety may be involved.

Most studies performed to further delineate the natural history of HCV have involved adult cohorts; therefore, further research on the ultimate outcome of infection during childhood is clearly needed.

See also Pediatric Hepatitis A and Pediatric Hepatitis B.

Hepatitis C virus is a member of the Flaviviridae family of RNA-containing viruses. Thus, it is not integrated into the host genome.

Although the liver is the primary target of infection, studies to better define the steps of hepatitis C virus infection are greatly hampered by the lack of a suitable animal model for such studies (the only animal known to be susceptible to hepatitis C virus is the chimpanzee). A tissue-culture system using recombinant DNA technology was recently developed and has advanced the scientific knowledge base considerably, including early forays into vaccine development.

The primary immune response to hepatitis C virus is mounted by cytotoxic T lymphocytes. Unfortunately, this process fails to eradicate infection in most people; in fact, it may contribute to liver inflammation and, ultimately, tissue necrosis.

The ability of hepatitis C virus to escape immune surveillance is the subject of much speculation. One likely means of viral persistence relies on the presence of closely related but heterogeneous populations of viral genomes. Further studies of these quasi-species enable classification of several genotypes and subtypes, which may have clinical implications.

Direct percutaneous exposure is the primary means of transmission. Blood transfusions are another means of transmission.

Historically, most hepatitis C virus infections result from blood transfusions. The risk of transfusion-borne hepatitis C virus began to decline in 1986, when surrogate-marker screening of blood donors started. Further declines were noted after the introduction of hepatitis C virus–directed antibody screening in 1990 (first generation) and 1992 (second generation). The current risk of transfusion-derived hepatitis C virus is estimated to be 1 case in every 100,000 units transfused.

Currently, the use of injected drugs is the most important epidemiologic risk factor, probably accounting for around 50% of both acute and chronic infections. Other parenteral routes may be involved.

Hemodialysis is a possible cause of hepatitis C virus infection. Health care employees may be accidentally exposed. Tattooing, body piercing, and acupuncture with unsterile equipment are possible routes of infection.

The risk of sexual transmission appears to be low, even among individuals with multiple sex partners. However, the presence of coexisting sexually transmitted diseases (eg, human immunodeficiency virus [HIV] infection) appears to increase the risk.

Vertical transmission may occur. Perinatal transmission is possible and affects an estimated 5% of babies born to mothers with hepatitis C virus infection. The risk is higher for babies born to mothers who are co-infected with hepatitis C virus and HIV or hepatitis B virus.[1]

Density of viral infection with hepatitis C virus affects the likelihood of transmission from mother to child in utero. While density of approximately 100 particles per milliliter produced no vertical transmission to the baby, 1 million particles per milliliter resulted in a transmission rate of 36%.[2] Overall, transmission to babies was 6% in mothers who were hepatitis C virus antibody–positive and 10% in mothers who were hepatitis C virus RNA–positive. Breastfeeding is not contraindicated for mothers with hepatitis C virus infection.

Approximately 10% of adults with hepatitis C virus infection have no identified risk factor for infection.

An estimated 30,000 new hepatitis C infections occur annually in the United States, although only 25-30% are diagnosed. Since the 1980s, acute infections have declined by more than 80%. Nearly 4 million Americans, or about 2% of the US population, are infected with hepatitis C virus. Although the worldwide prevalence varies considerably by geographic region, more than 3% of the global population is infected.

Race-, sex-, and age-related demographics

With respect to the frequency of infection worldwide, significant racial differences are observed. In the United States, infection is more common among members of minority populations than in other groups. The effect of ethnic background on the risk of significant liver disease is undefined, but patients of African descent do not respond as well to therapy.

Hepatitis C virus infection is far more common in males than in females. Females have been reported to have a higher rate of infection from blood product transfusions and a lower rate from intravenous drug and alcohol abuse compared with males. Females may have less evidence of liver damage (liver enzyme levels, fibrosis) and high rates of spontaneous viral clearance.[3]

In the United States, the highest incidence is among individuals aged 20-39 years, and the highest prevalence is among those aged 30-49 years. The age at time of initial infection likely has important implications on the natural history of infection because individuals who are infected at a younger age tend to have a decreased risk of progression to cirrhosis and hepatocellular carcinoma.

Acute fulminant hepatitis C virus infection is rare, but more than 80% of acutely infected individuals develop chronic hepatitis. Most patients chronically infected with hepatitis C virus remain asymptomatic and do not have significant liver disease. The prognosis is guarded for those who have hepatitis C virus–related complications such as hepatocellular carcinoma and liver failure.

In more than 20% of adults with chronic infection, progression to cirrhosis occurs an average of 20 years after initial infection. Cirrhosis poses a secondary risk of portal hypertension, liver failure, and other complications. Hepatitis C is now the leading reason for liver transplantation in the United States. In 1-5% of patients, most of whom have underlying cirrhosis, hepatocellular carcinoma (HCC) is diagnosed an average of 30 years after initial hepatitis C virus infection. Annually, hepatitis C virus infection accounts for 8,000-10,000 deaths in the United States.

Instruct the patient to avoid all alcohol use. Inform the infected patient about the health practices listed in Deterrence/Prevention. The patient and other household members should be vaccinated against hepatitis A and B viruses.

For patient education information, see the Hepatitis Center and Liver, Gallbladder, and Pancreas Center, as well as Hepatitis C.

The incubation period of hepatitis C virus (HCV) infection varies widely, with a mean of 7-10 weeks and a range of 2-20 weeks. Infections are often inapparent or subclinical. Only 25-35% of patients have nonspecific symptoms such as weakness, malaise, and anorexia; likewise, patients with chronic HCV infection often have few or no symptoms. Fatigue is reported most often.

Screen patients for HCV infection if any of the following applies:

• History of illegal injected drug use

• Transfusion with clotting factor concentrates before 1987

• Transfusion with blood or blood components or receipt of organ transplants before July 1992

• Use of HCV-contaminated blood from a donor

• Long-term hemodialysis or persistently abnormal serum alanine aminotransferase (ALT) levels

• Needle sticks, accidents with sharps, or mucosal exposures to HCV-positive blood

Considering HCV testing in patients with HIV infection may be prudent, especially in those who acquired HIV through intravenous drug use. HCV is more easily transmitted than HIV, and the 2 viruses are often co-infections.

Approximately 25% of patients with acute HCV infection have jaundice, whereas less than one third have hepatomegaly. Some patients with chronic infection have findings consistent with chronic liver disease; these include hepatomegaly, ascites, splenomegaly, and spider nevi.

Complications may include the following:

• Fulminant hepatitis (rare)

• Cirrhosis, which may result in portal hypertension and liver failure

• Hepatocellular carcinoma

Extrahepatic manifestations may include the following:

• Porphyria cutanea tarda

• Sialadenitis resembling Sjögren syndrome

• Mooren corneal ulcers, a form of chronic ulcerative keratitis

• Type II cryoglobulinemia

• Membranoproliferative glomerulonephritis

• Non-Hodgkin lymphoma

Both acute and chronic hepatitis C virus (HCV) infections are often asymptomatic; therefore, the diagnosis often relies on the identification of a potential risk factor and on subsequent screening for HCV-directed antibodies. Obtaining serum alanine aminotransferase (ALT) levels may be helpful.

Genotyping of HCV has proven to be a useful clinical tool, as the response to therapy and prognosis is influenced by the viral genotype. Genotype 1 is less than half as likely as other genotypes to respond to therapy, and combination therapy regimens vary depending on the different genotypes. In addition, early work by one group suggests that alpha-fetoprotein may have a prognostic significance, at least for genotypes 1 and 4; the likelihood of treatment failure was 6 times higher for patients with serum AFP above the median value (5.7 ng/ml).[4]

Imaging studies are not generally warranted to establish the etiology of hepatitis. However, ultrasonography is useful to monitor for HCV-related complications.

The European Association for the Study of the Liver updated their Hepatitis C Treatment Guidelines.[5]

The new guidelines include the following:

• Anti-HCV antibodies are the first-line diagnostic test for HCV infection.

• In the case of suspected acute hepatitis C or in immunocompromised patients, HCV RNA testing should be part of the initial evaluation.

• If anti-HCV antibodies are detected, HCV RNA should be determined by a sensitive molecular method.

• Anti-HCV-positive, HCV RNA-negative individuals should be retested for HCV RNA 3 mo later to confirm true convalescence.

• Rapid diagnostic tests can be used instead of classical enzyme immunoassays to facilitate anti-HCV antibody screening and improve access to care.

• If anti-HCV antibodies are detected, HCV RNA should be determined by a sensitive molecular method to identify patients with ongoing infection.

• HCV RNA detection and quantification should be made by a sensitive assay with a lower limit of detection of ≤15 IU/ml.

See also Pediatric Hepatitis A and Pediatric Hepatitis B.

Hepatitis C virus–directed antibodies may be detected. Antibody screening using enzyme immunoassay (EIA) is inexpensive and reliable; generally, this is the screening test of choice for diagnosis. Recombinant immunoassay (RIBA) can then be used to confirm positive EIA results.

The US Food and Drug Administration (FDA) has approved OraQuick HCV Rapid Antibody Test, which uses a venipuncture whole blood sample and provides results in approximately 20 minutes.[6] The test can be used for persons at risk for hepatitis or for those with signs or symptoms of hepatitis.

Hepatitis C virus RNA may be detected with the polymerase chain reaction (PCR) test. Several FDA-approved test kits that can be used for blood product screening or diagnostic testing are currently available. (Kits are not usually approved for both uses.) Hepatitis C virus RNA is usually detectable within 1-2 weeks of exposure. Quantitative assays are available, but hepatitis C viral load has not been definitively shown to be useful in predicting outcome (unlike HIV viral load). It may be useful in predicting risk of recurrence in transplant recipients.

PCR testing is useful to confirm positive EIA results in the setting of indeterminate RIBA test results and to distinguish between resolved and chronic HCV infection in patients with positive EIA and RIBA results.

Other viral serologic tests may be useful in ruling out other causes of hepatitis, which can be present alone or in combination with hepatitis C virus.

• Hepatitis A virus immunoglobulin M (IgM) and immunoglobulin G (IgG)

• Hepatitis B virus surface antigen and antibody, core antibody

• Cytomegalovirus (CMV) IgM and IgG (and/or CMV in urine cultures)

• Epstein-Barr virus IgM and IgG

• HIV IgG enzyme-linked immunoassay (ELISA)

Acute infections

The peak serum ALT level is less than 2000 IU/mL in most patients with acute HCV infection, and 50% have a peak serum ALT level of less than 800 IU/mL. Overall, this peak is generally less than that seen in hepatitis A or B infections.

HCV-directed antibodies are generally detectable approximately 6-8 weeks after exposure; however, as many as 5% of infected patients do not produce antibodies.

Chronic infections

Many patients have normal serum ALT levels, although these levels may significantly fluctuate over time. Once present, HCV-directed antibodies generally persist.

Congenital infections

Infants born to mothers with HCV infection deserve special consideration.[7] Definitive serology cannot be obtained until age 9-15 months. Most experts recommend waiting until after age 12 months to obtain antibody levels, with follow-up testing for any positives at that time.

Testing with real time PCR (RT-PCR) for HCV RNA is sensitive after the first 1-2 months of life; 95% of infants exposed will be uninfected and a negative result at this early point can be reassuring for the family. An argument can be made for not testing for HCV RNA because of cost considerations, however, and because even if the child is infected, treatment is rarely needed until the second decade of life.

Spontaneous clearance can occur (up to 30% of infected infants) but is rare beyond age 3 years. Children who clear infection are negative for HCV RNA but remain antibody-positive.

Liver biopsy is generally not used to diagnose hepatitis C virus. However, it is the most accurate method of evaluating the extent of hepatitis C virus–related liver disease. Liver biopsy is recommended for all patients before they start antiviral therapy.

In patients with chronic HCV infection, inflammatory cells accumulate in the portal tracts. They may also have foci of inflammation accompanied by necrosis in the parenchyma. Subsequently, the margins of the parenchyma and liver tracts become inflamed, and liver cell necrosis results.

Ultimately, if the infection progresses, inflammation and necrosis may lead to fibrosis. Mild fibrosis is confined to the portal tracts and adjacent parenchyma, whereas severe fibrosis is associated with bridging between the portal tracts and hepatic veins.

Eventually, fibrosis can progress to cirrhosis, when the fibrous septa separate the liver into nodules.

For acute hepatitis C virus (HCV) infection, supportive care is the mainstay of treatment. Early initiation of antiviral therapy is not defined.

In chronic HCV infection, the goal is to identify complications and suitable candidates for antiviral therapy. The purpose of antiviral therapy is to ameliorate symptoms and reduce the risk of progressive liver disease. Consultation with a gastroenterologist may be indicated.

Long-term monitoring is essential because the risk of liver cancer is still high, even in sustained virologic responders.[8] In children, a well-defined interval for monitoring is not known, but every 6-12 months is probably reasonable to assess alanine aminotransferase (ALT) levels and clinical status.

Serum ALT levels have no consistent relationship to liver histologic findings. Longitudinal assessment of hepatitis C virus RNA provides a strong correlation with liver histologic results but is a weaker predictor of rate of progression.

Consider liver transplantation in patients with advanced liver disease. Surgical intervention may also be necessary for complications such as portal hypertension and hepatocellular carcinoma (HCC).

See also Pediatric Hepatitis A and Pediatric Hepatitis B.

The initiation of treatment is a complex decision involving knowledge of the patient's HCV genotype, compliance and social support, comorbid psychiatric conditions (depression can be worsened significantly by treatment), and progression of liver disease. Children younger than 3 years should not be treated due to a lack of approved medications and the possibility of spontaneous clearance of infection without therapy.

Identify suitable candidates for antiviral therapy, although all patients with chronic infection are potential candidates. Treatment is recommended for patients with chronic infection who have a persistently elevated serum ALT level, portal or bridging fibrosis, and at least moderate inflammation and necrosis at liver biopsy.

Consider treatment for other patients on an individual basis. Do not use antiviral therapy to treat patients with decompensated cirrhosis.

For individuals exposed to hepatitis C virus (HCV), passive immunization is not recommended. No vaccine has been developed for hepatitis C virus. People with HCV should be vaccinated against hepatitis A and B virus to prevent worsening of liver disease. Household contacts of children with HCV should be vaccinated against hepatitis A virus.

Discourage users of intravenous drugs from sharing needles. Adhere to universal precautions. Breastfeeding is not contraindicated for mothers with HCV infection. There is no need to bar children with HCV infection from attending daycare.

Infected patients with multiple partners should use barrier protection during sex. No special precautions are needed for monogamous relationships.

Instruct the patient not to share personal care articles such as toothbrushes or razors.

Blood, organ, or sperm donation from patients with hepatitis C virus infection is not permitted.

Long-term monitoring is essential in patients with chronic HCV infection because the risk of liver cancer is high, even in sustained virologic responders.[8] The prothrombin time is useful for assessing liver function. The serum alpha-fetoprotein assay is a potential screening test for HCC. Ultrasonography is potentially useful to monitor for hepatitis C virus–related complications such as portal hypertension and HCC.

The first direct-acting antiviral drugs were approved for adolescents in 2017. Sofosbuvir (Sovaldi) and the combination product, ledipasvir/sofosbuvir (Harvoni), are approved for chronic HCV infection in pediatric patients aged ≥12 years or who weigh at least 35 kg.

Sofosbuvir is indicated for HCV genotypes 2 or 3 and is used in combination with ribavirin. An open-label study was conducted in adolescents (n=52) who received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. Sustained virologic response at 12 weeks (SVR12) was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4.[9]

Ledipasvir/sofosbuvir is indicated for HCV genotypes 1, 4, 5, or 6. In an open-label study of adolescents (n=100) with HCV genotype 1, SVR12 was reached in 98%. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment.[10] The safety and efficacy of ledipasvir/sofosbuvir for treatment of HCV genotypes 4, 5, or 6 infection in adolescents was based on data showing similar systemic exposures to ledipasvir/sofosbuvir in adults and adolescents with HCV genotype 1 infection, as well as similar efficacy and exposures across HCV genotypes 1, 4, 5, and 6 in adult.[11]

Glecaprevir/pibrentasvir was approved for adolescents in April 2019. The safety, efficacy, and pharmacokinetics of glecaprevir/pibrentasvir in HCV genotypes 1, 2, 3, or 4 infected pediatric patients aged 12 years and older or weighing at least 45 kg was based on data from an open label trial in 47 subjects without cirrhosis aged 12-18 years who were either treatment-naïve (n=36) or treatment experienced (n=11).[12]

Alpha interferon (IFN) results in a sustained response in fewer than 20% of patients, and adverse effects are often problematic. More recently, the addition of oral ribavirin to IFN therapy has improved the sustained response rate to 40-50%. Some research suggests that the dose of interferon might be lowered in genotypes 2 and 3, if ribavirin is used in combination. However, adverse effects remain a problem, and the response rate is lower for individuals infected with genotype 1, the most common genotype that causes infection, and the less common genotype 4.

For patients with HCV genotype 1 who do not have a sustained response to therapy with peginterferon–ribavirin, a new treatment option is emerging. Though its role in pediatric HCV needs to be further defined, studies show that the potent oral HCV-protease inhibitor boceprevir is an effective treatment option for previously treated patients as well as untreated patients when used in addition to standard therapy as compared to standard therapy alone.

Pegylated IFN (the addition of polyethylene glycol to the drug) results in significantly higher rates of response, especially with non–genotype 1 hepatitis C virus (HCV) infections.

Peginterferon alfa-2b (PEG Intron) plus ribavirin (Rebetol) is approved for children aged 3 years or older, whereas peginterferon alfa-2a (Pegasys) plus ribavirin (Copegus) is approved for children aged 5 years or older.

One long-term study found that peginterferon was associated with significantly lower height, weight and BMI, which largely recovered when therapy was discontinued. However, height remained significantly lower for age in children treated for 48 weeks or more.[13]

Class Summary

Direct-acting antiviral (DAA) drugs interfere with specific steps in the HCV replication cycle through a direct interaction with the HCV genome, polyprotein, or its polyprotein cleavage products.

Sofosbuvir (Sovaldi)

Sofosbuvir is a nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition in turn suppresses viral replication. It is indicated for the treatment of chronic HCV genotypes 2 or 3 infection in pediatric patients aged ≥12 y or weighing at least 35 kg without cirrhosis or with compensated cirrhosis. It is used in combination with ribavirin.

Ledipasvir/sofosbuvir (Harvoni)

Ledipasvir inhibitors HCV NS5A protein, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition in turn suppresses viral replication. The combination is indicated for pediatric patients aged ≥12 y or weighing at least 35 kg with hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.

Glecaprevir/pibrentasvir (Mavyret)

Glecaprevir is a HCV NS3/4A protease inhibitor. NS3/4A protease is necessary for proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. Pibrentasvir is a HCV NS5A inhibitor. NS5A is essential for viral RNA replication and virion assembly.

Glecaprevir/pibrentasvir is indicated for treatment-naïve adolescents who are 12-17 y old or weigh at least 45 kg (99 lb) with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis or with compensated cirrhosis. It is also indicated for treatment-experienced adolescents with HCV genotype 1 who have been previously treated with a regimen containing either an NS5A inhibitor or an NS3/4A protease inhibitor, but not both. An 8-week regimen is approved for treatment-naïve patients with any genotype and for treatment-experienced patients with genotypes 1, 2, 4, 5, or 6 who had prior treatment with peginterferon, ribavirin, and/or sofosbuvir.

Class Summary

Interferons (IFNs) are synthetically derived from a class of proteins that is produced and released by cells after viral invasion. They stimulate the production of another protein that inhibits viral replication. The nucleoside analogue ribavirin has some antiviral activity against hepatitis C virus, although improvements are not typically sustained after monotherapy is discontinued. However, the use of ribavirin in combination with IFN alpha is more effective than either drug alone and provides sustained responses.

Ribavirin (Rebetol, Copegus)

Ribavirin inhibits viral replication by inhibiting DNA and RNA synthesis. It is administered as combination therapy with IFN alpha-2b. Ribavirin may potentiate the effects of IFN alpha, improving sustained-response rates with HCV.

Peginterferon alfa-2a (Pegasys)

Pegylated IFN is used in combination with ribavirin to treat patients with chronic HCV infection who have compensated liver disease and have not previously received IFN alfa. Pegasys consists of IFN alfa-2a attached to a 40-kd branched PEG molecule (alfa-2b has a smaller 12-kd PEG molecule and is made from IFN alpha-2b). It is predominantly metabolized by the liver.

Several recent small clinical trials have shown that PEG-IFN used in combination with ribavirin is superior to standard IFN therapy. Which populations these recommendations can be extended to (the trials involved mostly HIV/HCV coinfected individuals) and whether alfa-2a is better than alfa-2b or vice versa is not yet clear.

It is indicated as part of a combination regimen with other HCV antiviral drugs in children aged >5 y with compensated liver disease.

Peginterferon alfa-2b (PEG Intron)

E coli recombinant product. Used to treat chronic hepatitis C in patients not previously treated with interferon alfa who have compensated liver disease. Exert cellular activities by binding to specific membrane receptors on cell surface, which in turn may suppress cell proliferation and may enhance phagocytic activity of macrophages. May also increase cytotoxicity of lymphocytes for target cells, and inhibit virus replication in virus-infected cells.

It is indicated combination with ribavirin in children aged ≥3-17 y with compensated liver disease.

Interferon alfa-2b (Intron A)

INF alfa-2b is a protein product manufactured with recombinant DNA technology. Its mechanism of antiviral activity is not clearly understood. However, modulation of host immune responses enhances cytolytic T-cell activity, stimulates natural killer cell activity, and amplifies HLA class I protein on infected cells. Its direct antiviral activity activates viral ribonucleases, inhibits viral entry to cells, and inhibits viral replication. A direct antifibrotic effect has been postulated.

Prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 4 mo, discontinue treatment. If a response occurs (as measured by clinical improvement, a reduction in HCV viral load, or histologic improvement on liver biopsy), continue treatment until no further improvement is observed.

Whether continued treatment after that time is beneficial remains unknown. Some studies have found some salvage regimens with PEG-IFN to be of benefit.

It is indicated in combination with ribavirin for treatment of chronic hepatitis C in children aged ≥3 y with compensated liver disease previously untreated with alpha interferon therapy and in patients aged ≥18 y who have relapsed following alpha interferon therapy.