Abstract
In the United States, the burden of hepatitis C virus (HCV) infection is disproportionately high among young adults including pregnant persons, resulting in increased infections among children as perinatal transmission remains the main route of HCV infection in children. Hence, in 2020, the Centers for Disease Control and Prevention (CDC) recommended universal HCV screening during each pregnancy. HCV infection in infancy is usually asymptomatic, so the diagnosis entirely relies on testing of perinatally exposed infants which, historically, included anti-HCV antibody testing at ≥18 months of age. However, nation-wide perinatal HCV testing rates have been suboptimal with significant loss to follow-up. To address this problem, in 2023, the CDC introduced early single HCV RNA testing at 2–6 months of age with an alternative for HCV RNA testing up to 17 months of age if not previously tested. The high sensitivity and specificity of the HCV real-time PCR laid the grounds for this policy shift. In this review, we highlight how these new CDC recommendations will enhance testing of infants and children and ultimately contribute to overall HCV elimination efforts. We also emphasize the role of all pediatric providers and obstetricians in implementing these new guidelines. Additionally, we offer our perspective and practical advice for testing of perinatally exposed infants and children. Currently, curative oral antivirals for HCV-infection treatment are approved for children ≥3 years of age. As pediatricians, advocating for children’s wellness, it is our utmost duty to ensure that every child exposed to perinatal hepatitis C has been tested, diagnosed, linked to care, treated, and achieved cure.
INTRODUCTION
Hepatitis C virus (HCV) infection remains a major health problem in the United States and worldwide [1, 2]. The prevalence of HCV infection in the United States is the highest among women of reproductive age leading to increased HCV infections among pregnant persons. Between 2009 and 2018, the annual rate of acute hepatitis C tripled from 0.3 to 1.2 per 100 000 population with the highest rate among persons 20–29 years of age (3.1 per 1 00 000) [3]. This is highly significant as perinatal transmission is the most common route of HCV infection in children. Risk of HCV perinatal transmission was estimated in a 2014 meta-analysis to be 5.8% (95% CI = 4.2%–7.8%), and 10.8% (95% CI = 7.6%–15.2%) for infants of mothers with HIV coinfection [4]. A most recent study reported perinatal HCV transmission rate of 7.2% (95% CI = 5.6%–8.9%) and 12.1% (95% CI = 8.6%–16.8%) among pregnant persons with HIV coinfection [5]. Maternal antiviral treatment during pregnancy is a promising intervention to prevent perinatal transmission; however, this practice is currently available in research settings only and has not been widely adopted. In 2020 the US Preventive Services Task Force recommended one-time HCV screening for pregnant persons similar to all asymptomatic adults 18–79 years [6]. This was followed by the Centers for Disease Control and Prevention (CDC) 2020 recommendations which addressed the vertical transmission risk and cast a wider net, recommending universal screening for HCV with each pregnancy as part of the prenatal care [7]. HCV infection in infancy is almost always asymptomatic; hence, diagnosis relies on screening of all infants exposed perinatally. Unfortunately, reliable and early detection of HCV-infected infants has been challenging with as many as 75%–90% of exposed infants are not tested or linked to care [8–10]. Prior recommendations for evaluation of perinatally HCV-exposed infants advised performing HCV antibody (anti-HCV) testing after 18 months of age to confirm perinatal HCV infection which has led to significant loss to follow-up and inadequate overall testing. Other potential barriers to adequate testing are lack of knowledge of maternal HCV infection and unfamiliarity with testing guidelines among providers and unawareness of perinatal transmission risk and testing requirements among mothers/caregivers. Studies have shown that rural residence was associated with lower rates of perinatal HCV testing [9, 11]; whereas higher rates were associated with maternal linkage to medical care for methadone treatment and HIV care [9, 12, 13]. Approval of curative direct-acting antiviral agents (DAAs) for children 3 years of age or older mandates early identification, diagnosis, and linkage to care of all children with perinatal HCV infection. One major step toward this goal is to simplify testing. In November 2023 the CDC released its first recommendations for HCV testing among perinatally exposed infants and children with an emphasis on early testing with a single HCV ribonucleic acid (RNA) test [14].
SUMMARY OF 2023 CDC RECOMMENDATIONS FOR PERINATAL HCV TESTING
The new CDC recommendations advise testing for all infants and children born to pregnant persons with current (with detectable HCV RNA) or probable (with reactive HCV antibody testing and unavailable HCV RNA) HCV infection. CDC recommendations prioritize timing of testing to 2–6 months of age with a single nucleic acid test (NAT) for HCV RNA; and similarly for 7–17 months of age if not previously tested. Children over 18 months of age who have not been previously tested should receive an HCV antibody test with a reflex to NAT for HCV RNA [14]. The alignment of testing time with the well-child visits starting at 2 months will provide multiple opportunities to perform testing at subsequent visits if testing was not done at the first visit. Given the high sensitivity and specificity of HCV RNA testing, the CDC recommended one single NAT test to rule out perinatal HCV infection in children less than 18 months of age, and if HCV RNA was undetectable, no further follow-up is required unless clinically indicated. Conversely, those with detectable HCV RNA should be evaluated by a healthcare provider with expertise in hepatitis C management with retesting before starting DAAs [14]. Figure 1 demonstrates a framework for a continuum of care for perinatal HCV from pregnancy throughout infant testing to cure.
Perinatal HCV care continuum. This cascade of care starts with universal prenatal HCV screening to identify maternal HCV infection; followed by key steps to identify, test, and diagnose exposed infants. HCV-infected infants and children are subsequently linked to HCV medical care for treatment to achieve cure. Efforts should focus on identifying and eliminating barriers (at the policy, institutional, provider, and patient levels) in each step of the perinatal HCV care continuum. Abbreviations: HCV, hepatitis C virus; RNA, ribonucleic acid; mo, month; Ab, antibody; DAAs, direct-acting antivirals.
The single-step testing will simplify the care model and likely expand care in resource-constrained settings. Early testing at 2–6 months of life is cost-effective and likely to increase the number of children evaluated for perinatal HCV. The higher rate of testing achievable in the first few months of life was highlighted in a study conducted in New Jersey and included 142 HCV-exposed infants born between 1998 and 2013. All children underwent testing with anti-HCV antibody and HCV RNA during the first 18–24 months of life. About 50% of the testing was performed in the first 4 months of life, by 10 months of age testing rate decreased to 5% and increased only to 16% by 17–18 months of age [15].
ROAD TO IMPLEMENTATION
The Role of Pediatricians, Family Medicine Physicians, and Obstetricians
Guidelines are a valuable tool to bridge the gap between clinical practice and evidence-based research but without stakeholders’ engagement and effective implementation they are rendered useless. Hence, it is our obligation as pediatricians, family medicine physicians, obstetricians, and allied healthcare professionals to familiarize ourselves with the new CDC perinatal HCV recommendations and adopt processes in our practices to apply them. Our approach should be viewed from a continuum of care lens with the first threshold being universal prenatal HCV screening for pregnant persons, followed by identification and testing of exposed infants/children, and finally linkage to care and treatment of HCV-infected children [16].
Universal screening during pregnancy and rescreening is cost-effective [17]. Testing pregnant persons at the first prenatal visit will maximize opportunities for education about HCV and appropriate testing for exposed infants. Testing should be repeated during pregnancy in case of ongoing intravenous drug use or other transmission risk. Women should receive an HCV antibody test with reflex quantitative HCV RNA if the antibody test is positive; if reflex to NAT testing is not utilized in your laboratory, advocate for its adoption to timely identify mothers with HCV viremia. Mothers with HCV infection should be referred for HCV care for evaluation and individualized decision-making treatment when appropriate. Preventive measures during pregnancy to minimize HCV transmission include performing amniocentesis instead of chorionic villous sampling when invasive prenatal testing is indicated. Additionally, during labor, avoidance of internal fetal monitoring, early artificial rupture of membranes, and episiotomy can prevent HCV transmission [18]. Maternal diagnosis of HCV infection should be well-documented in the mother’s chart and communicated to the pediatric team.
HCV infection in infancy is almost always asymptomatic [19, 20]; hence, diagnosis relies on universal screening of all exposed infants. Once an exposed infant is born, pediatric providers should be notified via a communication alert through EMR or hospital messaging system. The first task is to transfer maternal HCV diagnosis to the newborn infant medical chart and list Perinatal hepatitis exposure (ICD-10 code Z20.5) or similar diagnosis in the “Problem List.” In settings where exposed infants are referred to Pediatric Infectious Diseases specialists for evaluation and testing, the referral can be scheduled in advance before hospital discharge and the time and location of the provider office should be made available for the caregiver. In our institution, maternal prenatal testing is transferred automatically to the infant chart, and when a maternal reactive HCV antibody test is detected, an automatic EMR nurse communication order will be ordered to alert nurses to notify a Pediatric Infectious Diseases provider and a second alert will fire upon placement of discharge order to alert discharging provider to confirm that a follow-up appointment at 2 months of age has been scheduled. We suggest adopting a similar scheme to alert the newborn’s primary care provider about the HCV exposure and advise testing at 2 months. Upon discharge, mothers/caregivers of exposed infants should be educated about HCV infection, natural course, and prognosis and should be offered counseling about their infant’s HCV testing plan and provided written anticipatory guidance to be followed if the infant is HCV-infected [practical information is provided in Supplementary Table 1]. Previous studies showed an over 40% increase in testing rate when infectious disease consultation at birth and education, close follow-up, electronic medical record (EMR) documentation of HCV exposure at birth, and testing reminder are used [21, 22]. Equally important to the optimal evaluation of all HCV-exposed infants and children is the linkage to care and subsequent treatment. If there is no healthcare provider with expertise in pediatric HCV management, then coordination and referral to a specialist is warranted, with HCV RNA retesting recommended before starting DAAs therapy [14]. Telemedicine has been used effectively in adults to increase the capacity of hepatitis C care in rural and underserved areas [23, 24]. Similarly, utilizing telemedicine where specialty care is lacking will offer expert guidance to pediatric primary care providers to manage and monitor children with hepatitis C infection. Finally, complicated social circumstances and poor living conditions can adversely affect infant testing and linkage to care [11]. Hence, it is crucial to identify social determinants of health and address them through referral to social service providers to provide counseling, transportation, communications support, food security, and housing.
Operational Guidance for HCV Testing of Perinatally Exposed Infants and Children
The first step is to be familiar with which test to order according to the child’s age at initiation of testing. The minimum age of initiation of testing is 2 months and this should be by using NAT until the age of 17 months. From 18 months and up use antibody testing with reflex to NAT for HCV RNA PCR. For documentation and ordering tests, use ICD-10 diagnosis code Z20.5 (Perinatal Hepatitis Exposure). If HCV testing is available locally at your practice, familiarize yourself with the process of ordering. For both antibody and NAT testing, plasma or serum are optimal specimens. Ordering details and examples of national reference laboratories ordering details and CPT® (Current Procedural Terminology) codes are provided in Table 1. However, check with your laboratory to determine the appropriate code and the process for ordering a specific test. Turnaround time varies between reference laboratories ranging from 1 to 6 days. Correct interpretation of the test result is of utmost importance, as the cutoff level for detection for quantitative RNA PCR varies between laboratories, ranging between 10 and 15 international units (IU)/mL (1.0–1.18 log). All NAT-based assays are reported in IU according to WHO international standards (ISs) to facilitate comparability of results for different assays [25].
Recommended Hepatitis C Diagnostic Tests and Examples of Reference Laboratories Ordering Details and Procedural Codes
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Recommended Hepatitis C Diagnostic Tests and Examples of Reference Laboratories Ordering Details and Procedural Codes
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A testing pitfall one might encounter is when HCV RNA testing is ordered for children younger than 18 months: the laboratory may default to the adult HCV testing protocol and perform anti-HCV with reflex to RNA which will result in a positive anti-HCV result (due to transplacental acquired maternal antibodies). This may trigger needless parental anxiety when the positive antibody result is received, and sometimes leads to another blood draw due to an insufficient sample to perform the RNA test. Additionally, HCV antibody testing has several limitations. First, in case of acute infection and in immunocompromised individuals there might be a delay of up to 6 months before the test becomes reactive. Second, reactive antibody test results do not distinguish between active infection and past infection (spontaneously resolved or treated), thus are not useful to monitor therapeutic response to antivirals. Lastly, false reactive tests may occur.
Public Health Role in HCV Elimination Efforts
Following the successful national model of perinatal HIV and perinatal HBV elimination frameworks, we can build on and expand the existing resources to provide public support for healthcare providers and communities. Because of the public health importance, the CDC has identified children ≤3 years of age (indicating possible perinatal transmission) as a high-priority group for further investigations when resources are limited [26]. Hepatitis C infection is a notifiable disease in the United States but currently, perinatal HCV remains underreported [27]. Robust perinatal HCV surveillance data will inform and improve public health efforts to understand the burden of hepatitis C in the community, track cases, and facilitate linkage to care.
FUTURE DIRECTIONS TO HCV ERADICATION
Currently, DAAs are not approved for use during pregnancy and their use has been limited while safety and efficacy studies are ongoing. Pregnancy offers a unique opportunity for HCV diagnosis and treatment through reliable access to care. Integration of treatment into prenatal visits will achieve cure and avoid the burden of linkage to HCV care after delivery and eliminate the risk of loss to follow-up. Moreover, learning from the HIV model, adherence to therapy during pregnancy tends to be higher than outside of pregnancy. If DAAs are approved for use during pregnancy, this will potentially be an effective tool to prevent vertical transmission and subsequently eliminate perinatal HCV.
Another promising frontier is the development of novel simplified testing platforms including rapid point-of-care (POC) tests based on NAT for detection and quantification of HCV RNA [28]. Validation of these tests among children will further simplify testing and allow healthcare workers and laboratory technicians with limited training to perform testing at time of the clinic visit. Furthermore, platforms using capillary blood from finger or heel stick would void the need for venipunctures. To allow scale-up and universal adoption, POC testing has to be affordable and laboratories have to ensure high-quality testing. The adoption of POC testing can be further expanded outside the private practice clinics into the local public health clinics. This will provide a safety net for HCV testing for infants and children who were enrolled in WIC (Women, infants, and children) program or receiving routine immunizations in public health clinics.
CONCLUSIONS
The advent of the DAAs offering near 100% cure and advanced molecular viral testing technology are turning points in the HCV realm and have made the prospect of eradicating HCV infection a realistic target. However, a serious gap hindering this goal is the dismal fact that the majority of children exposed to perinatal HCV remain untested. The new CDC guidelines represent a paradigm change in perinatal HCV evaluation with prioritization of early single HCV RNA testing starting at 2 months of age. The early one-step testing to diagnose HCV infection is a well-positioned move to remove time and logistical barriers, fill in the huge gap in the evaluation of exposed children, and facilitate linkage to care for HCV cure. Moving forward, in parallel to clinicians’ and public health efforts to adopt the CDC’s perinatal HCV recommendations, research and quality improvement initiatives are needed to evaluate the uptake and implementation of the recommendations. Additionally, maternal studies to evaluate DAAs’ role in the prevention of perinatal HCV transmission and innovative POC testing platforms to maximize HCV testing will move us one step toward the overall goal of HCV elimination.
Supplementary Data
Supplementary materials are available at the Journal of The Pediatric Infectious Diseases Society online (http://jpids.oxfordjournals.org).
Notes
Acknowledgments. The authors would like to acknowledge Dr Ravi Jhaveri for his critical review of the manuscript draft and constructive feedback.
Financial support. No funding was received by any of the authors for performance of the work reported in this manuscript.
Potential conflicts of interest. The following author has the following conflicts to disclose: Dr Saleh received funding support from the Centers for Disease Control and Prevention contract 200-2022-15052 (75D30122C15052) and (75D30123P18282).
Data availability. The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
Supplement sponsorship. This article appears as part of the supplement “Viral Hepatitis Elimination in Infants, Children, and Pregnant Women,” sponsored by Gilead Sciences.
