The management of infants, children, and youth at risk for hepatitis C virus (HCV) infection

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The introduction of direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) in paediatric practice represents a paradigm shift in the management of chronic HCV infection in children ^[1][2]. The high efficacy of this treatment has increased the incentive to identify infected children and youth ^[1]-[3]. The American Association for the Study of Liver Diseases (AASLD), the Infectious Diseases Society of America (IDSA),  the U.S. Centers for Disease Control and Prevention (CDC), and the Society for Maternal-Fetal Medicine now recommend that women be tested for HCV infection during each pregnancy ^[4][5]. While this recommendation has not yet been formally adopted by the Society of Obstetricians and Gynaecologist of Canada (SOGC) ^[6], it is anticipated that HCV testing in pregnancy will become routine in Canada in the near future.

This statement provides guidance on the management of infants born to mothers with chronic HCV infection and of older children and youth who are at risk of acquiring HCV infection.

Epidemiology of hepatitis C virus (HCV) infection

A global HCV infection prevalence estimate of 1% (95% CI 0.8 to 1.1) was recently derived by comprehensive literature review of country-level data, with higher rates (≥2.9%) reported for Egypt, Gabon, Mongolia, Pakistan, Russia and Uzbekistan ^[7]. The estimate for Canada was 0.6% (95% CI 0.4 to 0.7). However, one Canadian modelling study which took vulnerable populations into account suggested a seroprevalence of 0.96% (95% CI 0.61 to 1.34) ^[8].

Risk factors for HCV infection among children and youth in Canada are shown in Box 1 ^[9]. Injection drug use (IDU) is the predominant risk factor and associated with at least two-thirds of new infections ^[3][10]-[13]. In a longitudinal study of street-involved youth in Vancouver, 10.9% of those seronegative at baseline seroconverted after a mean follow-up of 18.5 months, with IDU and syringe sharing implicated as independent predictors of infection ^[14]. The high prevalence of HCV among women in correctional facilities (~25% ^[9]), which is driven, in part, by the criminalization of IDU ^[5], is a major health concern both for these women and the infants they may bear in future. Government regulation of tattooing and body piercing parlours has reduced HCV infection risk in such settings, but suboptimal infection prevention practices in unregulated or non-professional settings still pose risks ^[9][10][16]. The risk of acquiring HCV infection from blood products or contaminated medical equipment in Canada is remote ^[17]. Sexual contact and casual household contact have comparatively minor roles in HCV transmission ^[2][9].

Transmission and natural history of HCV infection in infants, children, and youth

A recent systematic review demonstrated a vertical transmission (VT) rate of 5.8% (95% CI 4.2 to 7.8) from HCV-infected mothers without HIV-1 co-infection and of 10.8% (95% CI 7.6 to 15.2) with sub-optimally controlled HIV-1 co-infection ^[18][19]. Other factors that are correlated with higher VT risk include: higher maternal HCV viral titres, elevated alanine aminotransferase (ALT) in the year before pregnancy, maternal IDU, fetal scalp monitoring, prolonged rupture of membranes, infant female sex, and being the second-born twin ^[6][20]-[24]. The HCV genotype does not appear to influence VT risk ^[20][22].

Between 20% and 30% of neonates infected vertically clear the infection, usually by 2 to 3 years of age, with recurrence of viremia being rare ^[25]-[28]. Factors associated with spontaneous clearance include higher ALT during the first 2 years of life, infection with genotype 3, and presence of the interleukin 28B rs12979860 single-nucleotide polymorphism ^[29]. Of children who do not spontaneously clear, about two-thirds exhibit asymptomatic infection with intermittent viremia, normal ALT levels, and no hepatomegaly ^[25]. The remaining third have chronic active HCV infection with persistent viremia, elevated ALT, and hepatomegaly in some cases ^[25].

Acute HCV infection in children and adolescents is almost always subclinical ^[28]. Severe active hepatitis is reported in 1% to 6% of cases and decompensated liver disease in 0.5% to 1.8% of cases ^[30][31]. Factors associated with the progression to cirrhosis include genotype 1a, co-infection with HIV-1 or hepatitis B virus (HBV), and steatosis on liver biopsy. Hepatocellular carcinoma is rare, occurring almost exclusively in individuals with cirrhosis. Extra-hepatic manifestations, including membranoproliferative glomerulonephritis, sub-clinical hypothyroidism and autoimmune thyroiditis, and elevated antinuclear antibodies have been described in children, but are much less common than in adults.

Management of infants and children born to mothers with chronic HCV infection

Treatment as prevention

The AASLD and IDSA recommend treating women of reproductive age who have chronic HCV infection before they become pregnant, both for their own health and because this approach would likely eliminate risk for VT ^[4]. There are insufficient data at present to recommend treatment during pregnancy.

Impact of mode of delivery and breastfeeding on HCV transmission

A recent systematic review reported no difference in VT risk between vaginal delivery and elective or emergency Caesarean section (C-section) in 10 of 11 observational studies ^[32]. Based on this evidence, C-section delivery is not recommended solely on the basis of HCV infection ^[6]. Modifiable delivery-related interventions that promote the mixing of fetal and maternal blood, such as use of fetal scalp electrodes or episiotomy, should be avoided ^[21][23]. Amniocentesis has not been associated with significantly increased VT risk, but because data are limited, women should be counselled on potential risk ^[33].

Current data suggest that breastfeeding is safe in the HCV context. No increased risk of transmission through breast milk was observed in any of the 14 cohort studies included in a recent systematic review ^[32]. One possible explanation as to why transmission via breast milk never or rarely occurs is that gastric acid rapidly inactivates HCV ^[23]. Thus, breastfeeding should generally be encouraged in the HCV context unless a mother’s nipples are cracked, damaged, or bleeding, or if she is co-infected with HIV ^[6].

Diagnostic testing for HCV in infants and children born to mothers with chronic HCV infection

The HCV diagnostic testing strategy for infants born to mothers with HCV infection should be individualized (Table 1). HCV antibodies in infants may indicate placental transfer of HCV immunoglobulin G (IgG) rather than infection. In general, for infants in whom follow-up is assured, serology at 12 to 18 months of age is the preferred testing strategy. Over one-half of exposed uninfected infants will be seronegative by 6 months of age, and 95% will be negative by 12 months of age ^[34]. Infants with reactive serology at 12 to 18 months of age should undergo HCV polymerase chain reaction (PCR) testing.

If follow-up at 12 to 18 months of age cannot be assured, such as for infants of mothers who inject drugs or are adversely impacted by other social determinants of health, HCV PCR testing in early infancy is indicated. Also, HCV PCR testing may be reasonable in early infancy when there is significant parental anxiety (related to HCV transmission). For infants, HCV PCR testing should be done at ≥2 months of age because the assay sensitivity is limited before that age ^[34]. A negative PCR result after 2 months of age usually means that VT did not occur. However, serology should still be performed at 12 to 18 months of age to confirm antibody clearance ^[35]. Any child with a positive HCV PCR should be referred to a paediatric infectious diseases specialist or paediatric gastroenterologist with expertise in HCV management to determine whether infection is chronic.

Table 1. Interpreting HCV test results in infants and children born to mothers with HCV infection
Age	HCV antibody *	HCV RNA	Interpretation
<2 months	Reactive	Not detected	Too early to interpret as child may not yet be viremic if infected perinatally
≥2 months	Reactive	Detected	HCV infection is present; between 20% and 30% of infants will clear the infection by 2 to 3 years of age †
2 to 17 months	Reactive	Not detected	Because the sensitivity of HCV RNA PCR may be <100%, antibodies should be re-tested at ≥18 months of age. If still present, HCV RNA PCR should be repeated to ensure HCV has been cleared.
≥6 months	Non-reactive	§	No HCV infection
≥18 months	Reactive	Not detected	Spontaneous clearance of HCV infection or possible occult HCV infection ǂ
*   A two-tier serologic testing algorithm is used in many jurisdictions in accordance with AASLD recommendations [35]. For interpretation, see Table 2. †   HCV RNA should be repeated at 6 month intervals. When persistently detected for 6-months or longer, chronic HCV infection is likely. ǂ   Occult HCV infection is defined by detection of virus in peripheral blood mononuclear cells or in hepatocytes with negative HCV PCR in serum. Routine investigation for occult HCV infection is not currently recommended in children due to limited data on clinical significance. §  Children who are seronegative at ≥6 months of age do not require HCV RNA testing. AASLD American Association for the Study of Liver Diseases; HCV hepatitis C virus; PCR polymerase chain reaction; RNA ribonucleic acid

Management of children and youth at increased risk of horizontally acquired HCV infection

Preventing HCV infection in children and youth

The “Blueprint to inform hepatitis C elimination efforts in Canada”, published by the Canadian Network on Hepatitis C (CanHepC) in 2019, provides a comprehensive framework for HCV elimination in Canada ^[3]. Emphasis is placed on the need for specific efforts targeting populations experiencing vulnerability and marginalization (people who inject drugs; Indigenous peoples; people who are or have been incarcerated; immigrants and newcomers to Canada; men who have sex with men) (Box 1). The document also acknowledges the importance of evaluating the cost-effectiveness and acceptability of routine prenatal HCV testing in Canada. Evidence from the United States and France has suggested that routine screening in pregnancy is cost-effective ^[36][37], and the availability of highly effective treatments in Canada further strengthens the argument for routine screening in pregnancy to enhance both maternal and child health ^[38].

Street-involved youth, particularly those who inject drugs, account for most horizontally acquired HCV infections in Canada, and are a priority population for prevention and harm reduction initiatives ^[14][39], including needle and syringe exchange programs and other supervised safer drug services, opioid agonist therapy, and treatment as prevention ^[3][40][41]. Addressing homelessness and other social determinants of health, health education, and providing services that are stigma-free, culturally appropriate, and community-based are essential care components ^[3].

Which children and youth should be screened for HCV infection?

The Public Health Agency of Canada recommends a risk-based approach to HCV screening (Box 1)^[2]. Because most HCV infections are subclinical, the routine screening of all infants, children, and youth with one or more risk factors is recommended, regardless of symptoms.

Box 1. Risk factors for HCV infection in infants, children, and youth

Being born to a mother who is HCV-positive Being born in or having lived in a region with high HCV prevalence (e.g., East Asia and Pacific, Eastern Europe and Central Asia, Latin America and the Caribbean, the Middle East and North Africa, Sub-Saharan Africa) Injection, intranasal, or inhalational drug use with shared equipment Engaging in unprotected sexual behaviours where blood may be present (e.g., condomless anal intercourse) Being a victim of sexual assault Exposure to non-sterile medical, dental, or personal service equipment (e.g., unsafe tattooing or body piercing practices) Receipt of an invasive medical procedure in countries where infection prevention and control (IPC) practices are not standardized

Adapted from reference 2 Note: Populations who are disproportionately affected by HCV in Canada include Indigenous peoples, persons with a history of incarceration, individuals who are homeless or street-involved, men who have sex with men (MSM).

What HCV screening and testing should be performed in children and youth at risk of HCV infection?

The standard HCV screening and testing strategy involves screening for HCV antibody in serum and then performing HCV PCR testing on blood for those who are antibody positive ^[3]. In situations where follow-up is a concern, such as for street-involved youth, consider “reflex testing”, whereby an HCV PCR test is performed immediately for antibody-positive individuals, using the same blood sample or a second sample obtained from the initial blood draw ^[3]. One emerging strategy that could enhance uptake is point-of-care testing in a broad range of settings by a wide range of non-medical service providers, including peers ^[3]. See Table 2 for interpretation of test results. For individuals with ongoing risk who have spontaneously cleared infection or were cured with treatment, periodic testing by PCR is warranted. An interval of 6 to 12 months between tests has been suggested for this group ^[3].

Table 2. Interpreting HCV test results in children and youth
Antibody screening test *	Supplemental testing *	HCV RNA	Interpretation
Non-reactive	–	–	No HCV infection
Reactive or indeterminate	Non-reactive or indeterminate	Not detected	Inconclusive results consistent with a false-positive screening test or very recent infection. Follow-up serology should be performed at least 6 to 8 weeks after the initial result †
Reactive or indeterminate	Non-reactive or indeterminate	Detected	HCV infection is present
Reactive	Reactive	Not detected	Spontaneously cleared infection or previously treated and cured or occult HCV infection ǂ
Reactive	Reactive	Detected	HCV infection present
*    A two-tier serologic testing algorithm is used in many jurisdictions in accordance with the recommendations of the AASLD [35]. A negative screening test is interpreted as negative. A   supplemental test is performed when the screening test is reactive or indeterminate. †    If the follow-up test is again inconclusive, discuss with Infectious Disease or Microbiology ǂ     Occult HCV infection is defined by detecting the virus in peripheral blood mononuclear cells or in hepatocytes with negative HCV PCR in serum. Routine investigation for occult HCV infection is not recommended in children and youth due to limited data on clinical significance. AASLD American Association for the Study of Liver Diseases; HCV hepatitis C virus; PCR polymerase chain reaction; RNA ribonucleic acid

What is the role of the general paediatrician or family physician in management of HCV infection in children and youth?

HCV infection cannot be transmitted during the routine activities of daily living. Reassure parents and caregivers that there is no known risk of transmission in saliva, urine, or stool, and no need for special precautions at home. Child care attendance and participation in play activities and sports should be unrestricted, and parents are not obliged to notify day care staff or school authorities of their child’s HCV infection.

Children and youth with chronic HCV infection should undergo serologic screening for HBV and hepatitis A virus (HAV) infection. A hepatitis B vaccine series should be administered when hepatitis B surface antigen is negative and anti-HBV surface antibody titers are non-protective. HAV vaccine should be administered when HAV antibodies are not detected.

When a diagnosis of chronic HCV infection has been established, referral to a paediatric hepatologist, gastroenterologist, or infectious diseases physician with expertise in HCV management is warranted. Treatment recommendations are evolving. Although DAAs are not yet approved for use in children <12 years of age in Canada, studies in children have shown them to be well tolerated, safe, and effective ^[1][42]. Sustained virologic suppression rates between 97% and 100% have been consistently achieved in children as young as 3 years old, with various DAA combinations administered over 8 to 16 weeks ^[43]-[49]. Based on these clinical trial results, both the AASLD and IDSA recommend this treatment for all children ≥3 years of age and youth who have been diagnosed with chronic HCV infection ^[1].

Recommendations

•   All infants, children, and youth with one or more risk factors for HCV infection should undergo screening for hepatitis C virus (HCV) infection.

•   For infants born to HCV-positive mothers, the diagnostic testing strategy should be individualized.

• When loss to follow-up before 18 months is not a concern, HCV serology performed at 12 to 18 months of age without prior HCV polymerase chain reaction (PCR) testing is preferred.
• When loss to follow-up is a concern, HCV PCR testing at a minimum 2 months of age is recommended. Infants with early negative HCV PCR test results should still have HCV serology performed at 12 to 18 months to finalize their HCV status.

•   For youth at ongoing risk for infection, planned periodic testing should be performed at 6 to 12 month intervals.

• For youth who are seronegative at baseline, HCV serologic testing, with reflex HCV PCR testing if positive, is recommended.
• For youth who are seropositive and PCR-negative at baseline, periodic screening using HCV PCR is recommended.

•   Screening for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis A virus (HAV) infection should occur concurrently with HCV testing in children and youth with risk factors for HCV infection. Vaccination for HBV and HAV should be given if non-immune.

•   When a diagnosis of chronic HCV infection has been established, referral to a paediatric hepatologist, gastroenterologist, or infectious diseases physician with expertise in HCV management is warranted.

•   Breastfeeding by mothers with HCV should be encouraged and supported unless contraindicated due to co-infection with HIV or human T-lymphotropic virus type 1/2. Woman who have cracked or bleeding nipples should temporarily interrupt breastfeeding until healing has occurred.

•   Paediatricians and family physicians have important roles in educating youth regarding HCV infection risks and prevention, and in advocating to government and public health authorities for harm reduction interventions targeting at-risk youth, accessible treatments for HCV-infected children and youth, and routine prenatal screening for HCV.

•   The implementation of routine prenatal HCV screening in Canada should be strongly considered. This would help ensure postnatal treatment for all HCV-infected women as well as earlier identification and treatment for all vertically infected children.

Acknowledgements

This position statement was reviewed by the Social Paediatrics Section Executive and the Adolescent Health, Community Paediatrics, Drug Therapy and Hazardous Substances, Fetus and Newborn, First Nations, Inuit and Métis Health, and Nutrition and Gastroenterology Committees of the Canadian Paediatric Society. It has also been reviewed by members of the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC).

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CANADIAN PAEDIATRIC SOCIETY INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE

Members: Michelle Barton MD; Ari Bitnun MD; Sergio Fanella MD; Ruth Grimes MD (Board Representative); Laura Sauve MD (Chair); Karina Top MD

Liaisons: Ari Bitnun MD, Canadian Pediatric and Perinatal HIV/AIDS Research Group; Fahamia Koudra MD, College of Family Physicians of Canada; Marc Lebel MD, IMPACT (Immunization Monitoring Program, ACTIVE); Yvonne Maldonado MD, Committee on Infectious Diseases, American Academy of Pediatrics; Dorothy L. Moore MD, National Advisory Committee on Immunization (NACI); Howard Njoo MD, Public Health Agency of Canada; Isabelle Viel-Thériault MD, Committee to Advise on Tropical Medicine and Travel (CATMAT), Public Health Agency of Canada

Consultant: Noni E MacDonald MD

Principal author: Ari Bitnun MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.