Cathy, a 3-year-old girl adopted from China 3 months ago, is brought to the primary care office because her adoptive parents were notified that her biological mother was recently found to be infected with hepatitis C. Cathy has been apparently healthy, but her new parents want to know if she should be tested for hepatitis C and, if found to be positive, is there a treatment for this condition. The parents also expressed concern that hepatitis C might be contagious and wondered if there were any precautions they should take at home or that should be instituted at her daycare. They also want to know if there are any long-term complications from hepatitis C requiring ongoing monitoring and specialty care.
Significance of Hepatitis C Infection
Hepatitis C virus (HCV) was discovered in 1989 and was found to be the major cause of post-transfusion non-A, non-B hepatitis. HCV infection is the most common bloodborne pathogen in the united States (Center for Disease Control and Prevention [CDC], 1998) with a yearly incidence in the 1980s of 230,000 cases. With the advent of methods to screen the national blood supply, the yearly incidence has fallen to 25,000 cases annually. HCV is a ribonucleic acid (RNA) virus of the flavivirus family. It has nine genotypes that vary geographically, with genotype-1 being most prevalent in the united States. Genotyping of the virus is important because the response to treatment and long-term complications of cirrhosis vary by genotype, unfortunately, the virus tends to mutate rapidly in the host making it difficult for the host’s immune system to eradicate the virus resulting in chronic infection (Hochman & Balistreri, 2003). This mutation process also makes it difficult to develop an effective vaccine.
Epidemiology
Prevalence. The prevalence of HCV in the general population of the united States is estimated to be 1.8% (American Academy of Pediatrics [AAP], 2003). Although HCV is a reportable disease many individuals with acute infections are asymptomatic and, therefore, not diagnosed. Also, individuals at highest risk for infection (i.e., injection drug users) may not readily seek health care and diagnosis (Kirn, 2002). According to the National Health and Nutrition Examination Survey (NHANES), 3.9 million of the non- institutionalized or incarcerated population has been infected with HCV, and 74% of them have a chronic infection (Alter et al., 1999). In the pediatrie population under 12 years of age the seroprevalence is estimated to be 0.2%, and in adolescents between 12 and 19 years of age the seroprevalence is estimated to be 0.4% (AAP, 2003). Fifty to sixty percent of children with HCV develop persistent infections even though they are asymptomatic and do not have biochemical evidence of liver disease, but limited data indicates less than 10% (as compared to 60%-70% of infected adults) go on to develop chronic hepatitis and less than 5% develop cirrhosis (AAP, 2003). The long- term effects of persistent low level infection among children with HCV for 3, 4, and 5 decades is unknown at this time. In adults with chronic hepatitis C there is a l%-3% risk of hepatocellular carcinoma development after 30 years of infection (El-Serag, 2003), but the risk for individuals exposed during childhood verses adulthood are not known. Long-term cohort studies are needed to determine the risk and associated factors for these serious complications.
Risk factors. The major risk factor for virus acquisition is direct percutaneous exposure to blood from a HCV-positive individual. Hepatitis C is much less contagious than hepatitis B virus (HBV), with the risk of infection increasing significantly with either repeated percutaneous exposure to infected blood or infusion with large amounts of infected blood (U.S. Preventive Services Task Force [USPSTF], 2004). The average infection risk for HCV following a single parental exposure to HCV-positive blood is 1.9% as compared to a 30% infection risk following exposure to blood with HBV and a 0.3% risk of infection with a single exposure to blood with human immunodeficiency virus (HlV) (Henderson, 2003). Before 1990 blood transfusions or use of clotting factor concentrates were the most common routes of spread. Because of the exclusion of high-risk donors and testing of donated blood for hepatitis C antibodies, the risk of HCV from a transfusion is now less than 1 in a million transfused units of blood (AAP, 2003). All immune globulin products and clotting factor concentrates released in the united States are now also HCV negative.
Presently, the common risk factors for acquisition of HCV are parenteral drug abuse (60%-90% of infections), high-risk sexual behavior (1%-10% of infections), hemodialysis (10%-20 % of infections), and accidental exposure in health workers (1%) (AAP, 2003). Contamination of medical equipment for procedures in physician offices or specialty clinics resulting in outbreaks of HCV among treated patients has been reported due to ineffective sterilization procedures or reuse of syringes by medical personnel (CDC, 2003). Tattooing, body piercing, and use of shared razors have also been implicated in HCV transmission (Borkowsky, 2002). Perinatal transmission of HCV, although infrequent, is a significant cause of HCV in infants and young children, but many children and adolescents diagnosed with HCV have no identifiable source of infection (AAP, 2003).
Figure 1. Clinical sequelae of HCV. Acute HCV is generally benign; only 20% of infected children are symptomatic. However, 50- 60% of children with HCV develop persistent infection. Serious sequelae are infrequent but include cirrhosis (
In the united States the leading cause of HCV is the use of contaminated needles and equipment for illegal intravenous drugs. The prevalence of HCV infection among populations of injection drug users (IDUs) is estimated to be between 30%-90%, increasing with duration and frequency of use of parenteral drugs (Miller et al, 2002). use of contaminated needles and equipment also increases the risk of transmission of other blood-borne pathogens, especially HIV. It is estimated there are over 200,000 people with both HCV and HIV infections in the United States (Thomas, 2002). One study found that 88% of HIV-positive youth who were IDUs were also infected with HCV (Miller et al., 2002).
Perinatal HCV transmission. In pediatrics, maternal-fetal transmission accounts for most cases. The risk to the fetus of acquiring HCV from an HCV RNA positive mother at the time of birth is 5% (range, 0%-25%) versus a 95% risk of acquiring HBV from an HBVsAg positive mother (Hochman & Balistreri, 2003; Schwimmer & Balistreri, 2000). Fetal monitoring during labor and prolonged rupture of the membranes increase the risk of transmission of HCV. If the mother is co-infected with HIV then the risk of the infant acquiring HCV goes up to 14% (range 5%-36%) because HCV titers tend to be higher in women co-infected with HIV (Hochman & Balistreri, 2003). Mothers with HCV can breastfeed, as high HCV titers in breast milk have not been documented, but they should be counseled about its presence (AAP, 2003).
Clinical Manifestations of Infection
The incubation period for HCV infection averages 6 to 12 weeks (AAP, 2003). HCV RNA can usually be detected in serum 2 weeks after infection, and anti-HCV antibodies appear 4-8 weeks later. All people with HCV antibodies or HCV-RNA in their blood are considered to be infectious, but those individuals with higher titers are more infectious. Acute infections are usually clinically silent and symptoms, if present, indistinguishable from symptoms found with hepatitis A or B infection. Only 20% of affected individuals becoming jaundiced, and abnormalities in liver function tests (elevations in the serum aminotransferase levels) are usually less pronounced than found in people with acute hepatitis B infections (AAP, 2003). Infected children may complain of anorexia, malaise, fatigue, and abdominal pain during the acute phase. The acute phase is followed by resolution of symptoms although the serum aminotransferase levels may continue to fluctuate.
Persistent infection occurs in 50%-60% of infected children even in the absence of biochemical evidence of the liver disease (AAP, 2003). The clinical sequelae for HCV in children varies. The majority of children with chronic infections are asymptomatic, but a few (
Diagnostic Tests
Children complaining of abdominal symptoms, jaundice, or with a history of risk factors for hepatitis C should have a screening panel of blood work done including a complete blood count (CBC), sedimentation rate, amylase and lipase levels, and liver function tests (LFTs). LFTs determine the serum transaminases, which rise with any hepatocellular inflammation; the serum bilirubin levels that may increase if the hepatocytes are not able to metabolize bilirubin normally; the synthetic function of the liver as indicated by the serum albumin; the coagulation profile as reflected in the prothromin and partial thromboplastin times; and the metabolic functions of the liver as indicated by the serum glucose level (see Table 1). LFTs are usuallynormal in hepatitis C infections except for mild elevations of serum transaminase levels.
Table 1. Liver Function Tests (LFTs)
Table 2. Tests to Detect HCV
Specific screening test for HCV can be done in a child with known exposure or to determine the cause of elevated LFTs. The time from exposure to onset of viremia is generally 1 to 2 weeks, but there are no direct tests for the serum viral antigen of HCV. The two major types of tests available to detect for HCV infection are antibody assays for immunoglobulin (Ig) G anti-HCV (Alter, Kuhnert, & Finelli, 2003) (see Table 2). The initial screening for HCV is usually performed through an anti-HCV screening enzyme immunoassay (EIA) (USPSTF, 2004). Positive results should be confirmed by a recombinant immunoblot assay (RIBA). Both third generations of these tests are 97% sensitive and 99% specific (USPSTF, 2004). False negative results can occur early in the course of infection due to the possible long interval between exposure and seroconversion, and repeat testing may be indicated in children with high risk factors. At this time, the CJSPSTF recommends against routine screening for HCV infection in asymptomatic adults who are not at increased risk for infection. In addition, there is insufficient evidence to recommend for or against routine screening for HCV infection in adults at high risk for infection (CJSPSTF, 2004). These screening tests are unable to discriminate between persistent infection and resolved infection. No recommendations have been made for children regarding screening for HCV infection.
The Food and Drug Administration (FDA) has approved diagnostic Nucleic Acid Tests (NATs) for quantitative detection and genotyping of HCV RNA using reverse transcriptase-polymerase chain reaction (RT- PCR) (AAP, 2003). This test determines the presence of active viremia. HCV RNA can be detected in serum within 1 -2 weeks of exposure and before anti-HCV tests are effective or abnormalities in LFTs occur. Genotyping and quantifying viral load are important when assessing the possible value of antiviral therapy.
In infants born to anti-HCV-positive mothers, passively acquired maternal antibodies can persist for up to 18 months; therefore, infants must be retested after 18 months of age with either of these tests to determine active anti-HCV status. Consequently, HCV RNA testing is used to identify infection in infants early in life when maternal serum antibodies can interfere with other test results. Viral RNA may be detected intermittently early in the infection, so false negative results can occur.
Treatment
Children with acute HCV infection usually require only supportive care at home. Supportive care for the child with hepatitis includes rest, a healthy diet, avoidance of hepatotoxic drugs like acetaminophen and alcohol, and prevention of additional liver disease through active immunization against hepatitis A and B. Children with HCV should be followed every 6 to 12 months with serial LFTs to assess the degree of inflammation and measurement of serum alphafetoprotein (AFP) along with an abdominal ultrasound to screen for hepatocellular carcinoma. If the LFTs begin to rise, the viral load should be reassessed with a repeat RT-PCR. Children should not be excluded from daycare if they have HCV, but standard precautions regarding bloodborne pathogens should be practiced both in school and at home. Transmission among family members is uncommon but can occur from direct or inapparent percutaneous or mucosal exposure to blood (AAP, 2003). Adolescents should be educated about the risk of transmission of the infection to their sexual partners, the use of alcohol, and the hazard of parenteral drug use.
Most children infected with HCV will not have long-term complications. As stated before, only 50%-60% of children with HCV infection will develop persistent infection. Of these, less than 10% will develop chronic hepatitis, and fewer than 5% will develop cirrhosis. Therefore, the benefit of additional antiviral therapy is questionable at this time.
There are two specific therapies currently approved by the FDA for chronic hepatitis C infections in adults and recently approved for use in children with hepatitis C age 3 years and older.
Interferon therapy (interferon-alfa, pegylated interferon alfa- 2a, alfa-2b). Interferons are antiviral and immunomodulatory proteins. They are naturally produced by leucocytes in response to infectious agents and tumors. In virus-infected cells, interferons can produce antiviral proteins, inhibit synthesis of viral RNA, and allow recognition of the infected hepatocytes by cytotoxic T lymphocytes. It is manufactured by the recombinant method. The disadvantages of this drug are its parenteral route of administration and tolerable but frequent side effects (see Table 3). Its longer acting formulation, called pegylated Interferon, requiring once weekly infusion, is now available for adult use only (AAP, 2003; Hochman & Balistreri, 2003; Strader, Wright, Thomas, & seeff, 2004). Given by itself, interferon-alfa only resulted in a sustained decrease in viral load in 10%-20% of the adults treated, use of the pegylated interferon resulted in sustained response in 25%-39% of treated adults and lower rates for adults with genotype- 1, the most common genotype found in the united States (Fried et al., 2002). Treatment protocols require at least weekly infusions for 12 months.
Table 3. Adverse Effects of Interferon and Ribavirin
Ribavirin therapy. Ribavirin is a guanosine analogue. Although monotherapy showed no beneficial effects in the treatment of hepatitis C, it has a synergistic effect when used with interferon alfa-2b for the therapy of chronic hepatitis C. This combination therapy resulted in sustained response in 33% of adults with genotype 1 and approximately 80% of adults with genotypes 2 or 3 (AAP, 2003). An oral liquid formulation (Rebetol ), to be used in conjunction with interferon alfa-2b, has recently been approved by the FDA (Schering-Plough, 2004). Treatment for HCV genotype-1 virus requires 48 weeks and 24 weeks for genotype-2 virus.
To Treat or Not to Treat
There are several factors that make treatment of HCV in children controversial. In a follow-up study conducted in 460 children who underwent cardiac surgery before 1991 when blood donor screening was initiated, it was found that 15% of the children became anti-HCV positive (Vogt et al., 1999). Fifty-five percent of these positive children remained HCV RNA-positive indicating continued virus production, but only one child had abnormal liver enzymes. Forty- five percent of the children cleared the infection spontaneously. This study showed that over a 20-year time interval almost half the children had cleared the virus. In those who remained infected, the disease had a benign course. As stated before, the treatment is long (6-12 months) and involves the use of parenteral medications with frequent side effects that have to be closely monitored via blood tests.
There have been studies conducted recently that show that early treatment may give the best chance of eradicating the virus and preventing chronic hepatitis. In a small cohort of children with chronic hepatitis C, early initiation of antiviral treatment was associated with a sustained response rate independent of treatment type (Hartman, Berkowitz, Rimon, & Shamir, 2003). In a study of 44 adults treated with interferon, 42 of 43 patients treated within 3 months of acquiring infection or within 1 month of being symptomatic were able to eliminate the virus (Jaeckel, et al., 2001). Although this study did not include children, it highlights the importance of early diagnosis and referral of children to a pediatrie hepatologist for potential treatment.
Conclusion
There is no vaccine or universally effective treatment available for HCV. The prevalence of long-term complications of HCV acquired during childhood is unknown. Additional insults to the liver must be prevented whenever possible in children infected with hepatitis C. Due to the lack of effective treatment and the virus’s ability to mutate, universal screening is not currently recommended. Education against high-risk activities is the only available protection. Research into the management of HCV in children is currently active and should result in a better understanding of the risks associated with each virus genotype, the best practice guidelines for treatment, and, hopefully, an effective means of prevention. Combination therapies for hepatitis C that have improved treatment efficacy in adults should be tested in controlled clinical trials in children. Protease inhibitors, antisense oligonucleotides, and ribosomes are some of the alternative treatment modalities being explored.
Cathy’s adoptiue parents were told that giuen the maternal history of Hepatitis C infection Cathy should be screened for the presence of HCV infection with LFTs and an anti-HCV screening enzyme lmmunoassay (ElA). If the E/A test is positwe, she will be further screened with the RT-PCR to detect the level ofviremia and genotype. When the results of these tests are known, Cathy should be referred to a hepatologist for long-term follow-up. In the meantime, her parents should be reassured that there is minimal risk of contagion in the family or daycare setting, although uniuersal bloodborne pathogen precautions are recommended. The parents were also told that the frequency of long-term complications from HCV in children is thought to be low and careful follow-up will be instituted with these complications in mind. HCV does not alter a child’s growth or deuelopment.
References
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Fried, M.W., Shiftman, M.L., Reddy, K.R., Smith, C., Marines, G., Goncales, F. et al. (2002). Pegylated alfa-2a- plus ribavarin for chronic hepatitis C virus infection. New England Journal of Medicine, 347(13), 975-982.
Hartman, C., Berkowitz, D., Rimon, N., & Shamir, R. (2003). The effect of early treatment in children with chronic hepatitis. Journal of Pediatrie Gastroenterology and Nutrition, 37(3), 252- 257.
Henderson, O.K. (2003). Managing occupational risks for hepatitis C transmission in the health care setting. Clinical Microbiology Review, 76(3), 546-568.
Hochman, J.A., & Balistreri, W.F. (2003). Chronic viral hepatitis: Always be current. Pediatrics in Review, 24(121,399-409.
Jaeckel, E., Cornberg, M., Wedemyer, H., Santantonio, T., Mayer, J., Zankel, M. et al. (2001). Treatment of acute hepatitis C with Interferon alfa-2b. New England Journal of Medicine, 345(20), 1452- 1457.
Kim, W.R. (2002). The burden of hepatitis C in the United States. Hepatology, 26(5), 30-34.
Miller, C.L., Johnson, C., Spittal, P.M., Li, K., LaLiberte, N., Montaner, J. S., et al. (2002). Opportunities for prevention: Hepatitis C prevalence an incidence in a cohort of young injection drug users. Hepatology, 36(3), 737-742.
Schering-Plough. (2004). FDA approves Rebetol (ribavarin} oral solution for treatment of children with chronic hepatitis C. Kenilworth, NJ: Schering-Plough. Retrieved from www.scheringplugh.com/schering_ plough/news/ release.jsp?releaselD=485964.
Schwimmer, J.B., & Balistreri, W.F. (2000). Transmission, natural history, and treatment of hepatitis C virus infection in the pediatrie population. Seminars in Liver Disease, 20(1), 37-46.
Strader, D.B., Wright, T., Thomas, D.L. & seeff, L.B. (2004). Diagnosis, management, and treatment of hepatitis C. Hepatology, 39(4), 1147-1171.
Thomas, D.L. (2002). Hepatitis C and immunodeficiency virus infection. Hepatology, 26(5), 207-209.
U.S. Preventive Services Task Force (USPSTF). (2004). Screening for hepatitis C: Recommendation Statement. Rockville, MD: Agency for Healthcare Research and Quality. Retrieved from www.ahrq.gov/ clinic/ Srduspstf/hepcrs.htm.
Vogt., M., Lang, T., Frosner, G., Klinger, C., Sendl, A., Zeller, A. et al. (1999). Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. New England Journal of Medicine, 347(121,866-870.
Sona Sehgal, MD, is Pediatrie Gastroenterology/Hepatology Service Clinical Fellow, Yale-New Haven Hospital, New Haven, CT.
Patricia L. Jackson Alien, MS, RN, PNP, FAAN, is Professor, Yale university School of Nursing, New Haven, CT.
The Primary Care Approaches section focuses on physical and developmental assessment and other topics specific to children and their families. If you are interested in author guidelines and/or assistance, contact Patricia L. Jackson Alien at [email protected].
Copyright Anthony J. Jannetti, Inc. Sep/Oct 2004
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