Hepatitis C virus in childhood and pregnancy

Abstract

Infection with hepatitis C virus (HCV) represents a continued worldwide health concern. There are an estimated 50 to 71 million people living with HCV worldwide. This number continues to fall with availability of curative treatment, and there is now a stated goal to reduce infections by 90% and deaths by 65% worldwide by 2030. Annual mortality estimates for HCV and its complications range from 230,000 to 400,000. Although these longer term complications are more prevalent in adults than children, HCV in pediatric patients remains a public health concern.

An 8- to 12-week course of direct-acting antiviral medications can produce a sustained viral response rate of 95% to 99% (an increase from the 50% rate with prior pegylated interferon and ribavirin). Pregnant women and children represent 2 classes of patients for whom antiviral therapy has not been widely applied. Although children over 3 years of age now can be treated with direct-acting antivirals, pregnant patients are screened but not routinely treated for HCV. Close linkage to care during the prenatal period or after delivery with follow-up for mother and child remains paramount. In this review we highlight a brief history of HCV, the difficulty of assessing the burden of disease in pregnancy and childhood, the risk of mother-to-child transmission, the revised 2024 Centers for Disease Control and Prevention testing guidance, care in pregnancy, burden of children co-infected with HCV and hepatitis B virus or human immunodeficiency virus, treatment regimens for children and adolescents, and prospects for vaccine development.

1. A brief history of hepatitis C virus (HCV)

HCV was previously called non-A non-B hepatitis (NANBH). NANBH was postulated to be an infective agent that could cause chronic hepatitis, leading to cirrhosis and liver cancer that was not attributable to hepatitis A virus or hepatitis B virus (HBV).

At the time of Blumberg’s Nobel Prize for the discovery of HBV in 1976, it was realized that NANBH could be silently transmitted or present symptomatically with jaundice, dark urine, abdominal pain, nausea, vomiting, loss of appetite, fatigue, and fever.^{[1,2 and 3]} Additionally interferon injections at the National Institutes of Health that were used to treat HBV achieved NANBH cure in a subset of patients.^[4]

This virus was isolated, sequenced, and labeled HCV in 1989. This has allowed for screening of the blood supply and transplanted organs; the practice became widespread after 1992.^[1] The 2020 Nobel Prize in Physiology was awarded to Harvey J. Alter, who demonstrated that an unknown virus could cause hepatitis, Michael Houghton for the discovery of HCV, and Charles M. Rice who found that HCV alone could cause hepatitis. Currently there are 8 known genotypes with 86 subtypes, but all have a similar structure.^{[5,6,7 and 8]} HCV attaches to receptors, enters through binding to claudin 1 and occludin, is endocytosed through a clathrin-mediated process, and then fuses with a lysosome, which dissolves the envelope and capsid to release the ribonucleic acid (RNA) for replication and translation. The approximately 9,600 base positive-sense, single-stranded RNA molecule encodes 10 genes; these are translated into a single polyprotein that is cleaved by proteases encoded by human hepatocytes as well as by the virally encoded proteases NS2 and NS3/4A.^[9] The virions are assembled on the endoplasmic reticulum and then released by the hepatocyte to continue the infection.^[9,10]

2. Burden of HCV in childhood and pregnancy

2.1. Prevalence

HCV prevalence in children cannot be easily compared across countries because differing methodologies and tests have been used (RNA, antigen, and serology), but estimates are based on modeling of available data. Although country level estimates of prevalence exist, more granular age-based cohorts are not commonly found.^[11] Schmelzer and colleagues created a disease burden Markov model using historical prevalence estimates from 39 countries and inputted data from risk factors in 25 countries to create regression models for an additional 65 countries, allowing for an estimated global HCV prevalence in people 18 years and younger at 0.13% (95% confidence interval (CI), 0.08%–0.16%).^[12] Abdel-Gawad and colleagues reviewed available data and selected 20 studies (5 from Egypt, 3 from the United States, and 12 from other countries) comprising 48,963 children to create a composite weighted estimate for HCV seroprevalence at 0.904% (95% CI, 0.543%–1.355%) and noted that seroprevalence was higher in studies prior to 2010.^[13] The data are reproduced using a list of the countries in Table 1.^[13] The estimate from Abdel-Gawad and colleagues is in line with the estimated HCV infection prevalence of 0.1% to 2.0% of all children^[14] and 1% to 1.5% of North American children, estimated by Squires in 2017.^[15] Although in 2021, the Centers for Disease Control and Prevention (CDC) reported that there were only 199 new neonatal cases of HCV in the United States, infection rates in the United States tripled between 2010 and 2021 in persons aged 20 to 29 years, becoming 2.5 persons per 100,000, and sextupled in persons aged 30 to 39 years, becoming 3.5 persons per 100,000.^[16] Within the United States, there has been a 364% increase in the infection rate in individuals aged 12 to 29 years in Appalachia.^[17] The estimated prevalence of HCV is 1% to 8% in pregnant women, and mother-to-infant transmission rates are 3% to 10% of cases, resulting in about 60,000 neonatal cases per year.^[18] It is likely that the disease burden in women, children, and adolescents is not fully realized due to under or inconsistent testing and reporting.^[13,15]

Table 1.

Estimated HCV prevalence in children.

Country	HCV seroprevalence (%)	95% CI (%)
China	0.345	0.189 to 0.579
Columbia	1.400	0.565 to 2.863
Egypt	2.572	2.018 to 3.229
Germany	0.800	0.458 to 1.296
Italy	0.364	0.175 to 0.668
Mexico	0.889	0.243 to 2.260
Mongolia	1.485	0.867 to 2.367
Poland	1.300	0.694 to 2.213
Saudi Arabia	0.867	0.618 to 1.184
Turkey	0.568	0.117 to 1.651
United Kingdom	0.357	0.0433 to 1.284
United States	0.108	0.0721 to 0.155

This table reproduces Abdel-Gawad and colleagues’ estimates of HCV seroprevalence in selected countries for 2022. The estimated overall prevalence was 0.904% (95% CI, 0.543%–1.355%).^[13] HCV: Hepatitis C virus; CI: Confidence interval.

2.2. Disease course

Most transmission to children occurs perinatally and is no longer due to blood transfusions or dialysis; however, these remain possible routes of transmission. Spontaneous clearance estimates range from 65.9% by 5 years of age to 25% to 40% for children aged less than 2 years to 6% to 12% for patients over 2 years.^{[19,20 and 21]} Those who fail to clear detectable RNA in the blood for longer than 6 months are classified as having chronic HCV infection.^[20] At least 20% of adults with chronic infection will progress to cirrhosis and hepatocellular carcinoma (HCC). More recent data suggested that in adults the complication rate is closer to 32%.^[22,23] Pediatric cases have mild elevations in aminotransferases and, on biopsy, are generally not as histologically severe as adults. The complications of fibrosis, cirrhosis, liver failure, and HCC are rarer in children with HCV.^[14,18]

Several cohorts have investigated the prevalence of fibrosis and cirrhosis in children with HCV. The Pegylated Interferon +/– Ribavirin for Children With Hepatitis C (PEDS-C) trial contained 121 children aged 2 to 16 years who were treatment naive and were later treated with PEGinterferon alfa-2a and ribavirin. It featured enrollment biopsies that offer a survey of untreated HCV in children. The biopsies in this study showed minimal inflammation in 42%, mild in 17%, moderate in 38%, and severe in 3% of cases, with 2 children having cirrhosis and 5 bridging fibrosis; notably, steatosis was present in 44% of patients.^[24]

In a Japanese retrospective cohort of 348 patients, born between 1986 and 2015, from 65 centers, 147 patients had liver biopsies between 1995 and 2015 (mean age 8 ± 4.9 years).^[8] Within the cohort, 33% were F0, 58% were F1, and 9% had F2 fibrosis, but none were reported as F3 or F4 per the new Inuyama scale. No inflammation was seen in 5%, mild inflammation in 74%, moderate in 20%, and severe in 1%. A Russian cohort of 301 children less than 18 years of age, followed from 2014 to 2017, underwent liver biopsy, and 42% of those samples revealed bridging fibrosis or cirrhosis.^[25]

Published studies regarding the use of transient elastography to assess fibrosis in pediatric chronic HCV are limited. In a cohort of 35 children aged 12 to 17 years from Poland (63% male, 83% vertically infected, 60% treatment naive, 83% genotype 1, and 14% genotype 4), 31 out of 35 children (89%) had F0 or F1 (per the Meta-analysis of Histological Data in Viral Hepatitis scoring system) fibrosis whereas 4 out of 35 (11%) had F ≥2 fibrosis (with 2 having cirrhosis).^[26] A separate Italian cohort of 54 pediatric patients with chronic HCV reported that 26 of 29 patients who underwent treatment had pre-treatment elastography; 6 of those (23%) had abnormal liver stiffness (kPa > 7), with a median 9.1 kPa. Of the 29 patients, 27 completed therapy with 100% sustained virologic response (SVR); 17 underwent elastography post-treatment (median 16 years), with a median lower value of 7.9 kPa (7 kPa was used as the cutoff for abnormal stiffness).^[27] A cross-sectional Egyptian cohort of 50 patients from 2022 with chronic HBV (15 patients) or chronic HCV (35 patients) and biopsies underwent elastography; 43 of the patients had no or mild fibrosis with a mean ± standard deviation (SD) stiffness of 5.3 ± 1.2 kPa whereas the 7 patients with moderate or severe fibrosis on biopsy had a higher range of 7.3 ± 3.6 kPa. However, noting the size of the standard deviation, it appears that even those with more fibrosis could have a stiffness that might appear in the no or mild fibrosis range.^[28] A 23-patient cohort of children aged 10 to 18 years with chronic HCV who were treated with sofosbuvir/ledipasvir and achieved SVR demonstrated a decrease in transient elastography stiffness from a mean ± SD of 8.3 ± 3.8 kPa to 6.4 ± 2.3 kPa 1 year after completing therapy (P < 0.03).^[29] Taken together, the limited elastography data demonstrate that moderate and severe fibrosis is uncommon in children but can be assessed with transient elastography. These stiffness scores appear to improve with SVR.

2.3. Complications of HCV infection

HCV increases the risk of complications in pregnancy for mother and child. A review of the Ontario cohort in 2022 showed that, compared to women with a history of resolved HCV infection, those with an active infection in pregnancy had a higher risk of preterm delivery (18% vs. 12%, P = 0.0002), intrahepatic cholestasis of pregnancy (4% vs. 2%, P = 0.0013), and post-partum hemorrhage (9% vs. 5%, P = 0.0003).^[30,31]

Complications to the fetus include intrauterine growth restriction, low birthweight, and increased admission rate to the neonatal intensive care unit, with a higher need for respiratory support.^[18,32] There was a statistically significant (P < 0.001) lower fetal birth weight (median 3.119 kg (2.719–3.490 kg)) for children born to mothers with HCV RNA than in those who were RNA negative (median 3.300 kg (2.857–3.600 kg)).^[30] The complications of maternal infection can result in significant anguish, pain, and cost, both during pregnancy and if the infection is transmitted to the child.

2.4. Disease course: medical and psychiatric

Both children living with HCV and their caregivers express concern about mental and social health.^[14] Due to concerns about transmission, children are treated differently by both caregivers and also by peers or in school. In 2009, parents of children with HCV in a clinical trial were more likely to believe that their child’s health was poor and would worsen and limit family activities due to the HCV diagnosis.^[33] However, 50 non-cirrhotic adolescents with HCV who underwent sofosbuvir and ribavirin therapy (100% SVR after 12 weeks (SVR12) for genotype 2 and 95% SVR12 for genotype 3) achieved family-perceived improvement in quality of life and social functioning after completing treatment, suggesting that, with higher cure rates, the parent and patient self-perception in fulfilling the “ill” role with likely decrease.^[34]

3. Risk of mother-to-child transmission (MTCT) of HCV

Vertical transmission or MTCT accounts for 60% of cases and can occur in utero or intrapartum.^[2,14,15] The HCV incubation period is 30 to 60 d. Because pregnancy is a state of relative immunodeficiency, there is expansion of regulatory T cells with a shift to the Th2 cells within the Th1-Th2 balance. In this setting, it appears that HCV replication is enhanced during pregnancy; pregnant women are noted to have an increased viral load with reduced alanine aminotransferase levels.^[18] A retrospective cohort analysis comparing 1,780 women who were HCV RNA positive during pregnancy in Ontario, Canada demonstrated that women with HCV RNA had an MTCT risk of 3.5%.^[30] Another study demonstrated a 5.8% risk of transmission among children born to women who are both RNA and antibody positive.^[35] Ades and colleagues reviewed 3 European cohorts and found a transmission rate of 7.2% (95% CI, 5.6%–8.9%).^[19] Each maternal-fetal dyad is not the same and additional factors aside from high maternal viral load (>1,000,000 IU/mL) have been associated with increased risk of transmission. It has been reported, however, that maternal loads as low as 20,000 IU/mL can result in transmission; there is no truly safe level of HCV RNA in the blood aside from an undetectable level.^[36] However, it has been shown that human immunodeficiency virus (HIV) co-infection, female sex, and prolonged labor all increase the MTCT risk (Figure 1). The human leukocyte antigen class II diversity between mother and child, as well as an elevated NK cell presence, correlated with decreased MTCT risk whereas IL28B polymorphisms, breastfeeding, and invasive fetal monitoring did not correlate with MTCT.^{[18,37,38 and 39]} Prior studies showed no difference in HCV transmission in formula versus breastfed babies; this has been hypothesized to be the result of breast milk lipase generating free fatty acids from the HCV viral envelope, resulting in a virus with diminished infectivity.^[18] Mothers with HCV with cracked or bleeding nipples are asked to not breastfeed. Although maternal HBV and diabetes are not associated with MTCT, they may be associated with maternal progression to cirrhosis related to chronic HCV.^[39]

Figure 1.

Factors that alter MTCT risk. High maternal viral load, HIV co-infection (hypothesized to occur from regulatory T-cell expansion during pregnancy, allowing for increased HIV and HCV replication), and prolonged labor are known to increase risk of MTCT, whereas increased HLA diversity, specific HLA alleles, and increased NK cell presence are likely protective. HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; HLA: Human leukocyte antigen; MTCT: Mother-to-child transmission; NK: Natural killer.

4. Clearance

Spontaneous clearance or treatment of HCV can cure a patient. Antibodies to the virus which are secreted in response to HCV infection are not protective. Although antibodies suggest a current or prior infection, they are not diagnostic without assessment of detectable RNA to establish presence of the virus. Spontaneous clearance of viremia occurs in 13% to 18% of adults.^[40] Co-infection with HIV reduces the clearance rate to 5.0% to 8.6% of individuals.^[41]

A 2004 study by the European Paediatric Hepatitis C Virus Network examined a cohort of 266 children (240 with HCV alone and 26 with HCV and HIV), and investigators estimated that 20% of vertically infected children clear the infection, 50% are asymptomatic but chronically infected, and 30% are symptomatic with chronic infection.^[42] The study additionally noted that although hepatomegaly was the most common sign in children, it only occurred in 20% of cases. Ades and colleagues provided updated data from 1,749 children across 3 studies and found a clearance rate by 60 months (5 years) of 65.9% (95% CI, 50.1%–81.6%), although prior estimates listed 25% to 40% for children less than 2 years of age and 6% to 12% for those over 2 years of age.^{[19,20 and 21]}

5. Testing and screening

Since 2020 the CDC has recommended universal screening at least once per pregnancy.^[43] A cost-effectiveness analysis estimated a cost of $41,000 per quality-adjusted life year, with an increase in detection among neonates from 44% to 92%. Previously only antibody testing was recommended starting at 18 months of age, and the use of nucleic acid amplification tests (NAATs) prior to that time was left to the discretion of the pediatrician. Now the RNA NAAT is recommended for infants aged 2 to 6 months born to mothers with HCV or unknown HCV status. No follow up is needed for infants aged 2 to 6 months with a negative RNA test.^[44] The recommendations have also clarified that NAATs are recommended for children aged 7 to 17 months who were exposed but not previously tested due to concerns for the passive transmission of anti-HCV antibodies from infected mothers. Those 18 months and older are still recommended to undergo antibody testing and, if positive, automatically undergo a NAAT.

Early screening can be implemented to exposed and at-risk children; however, linkage to care through the primary care physician or pediatric gastroenterologist/hepatologist remains critical. Communication between the nursery, newborn intensive care, primary care pediatrician, and pediatric subspecialty teams within and between health systems is key to preventing loss to follow-up.^[16] In the Ontario cohort of 1,780 pregnant mothers who were HCV RNA positive, 1,364 infants (76.6%) had no HCV screening within the 2 years after birth.^[30] In view of these and other gaps in identifying infected persons, all individuals aged 18 to 79 years in the United States are recommended to undergo HCV screening at least once in their lifetime even if they do not have known risk factors.^[16]

Of note, despite chronic untreated HCV infection disqualifying individuals for military service in the United States, only the U.S. Navy and Marine Corps regularly screen recruits as of 2022.^[45] A study from 2016 did note that screening for HCV on recruitment of servicemen and servicewomen in the United States would result in cost savings for the U.S. Department of Defense as well as reduction in risk of transmission in the military blood donor pool.^[46]

The availability of point-of-care (POC) HCV testing might offer an additional means of reducing the timeframe from sample collection to result to a plan of care with the pediatrician. Since children in the United States are routinely screened before 1 and 2 years of age for lead and hemoglobin in the office, there exist 2 additional discrete time points when HCV could be detected and confirmed prior to the minimum age for therapy at 3 years. With the U.S. Food and Drug Administration–approval of the Xpert HCV test and the GeneXpert Xpress System (Cepheid, Sunnyvale, California, USA) on June 27, 2024, accurate RNA POC testing could now be deployed in emergency departments, urgent care, primary care, and even school clinic settings.^[47] Uptake of POC testing in the primary care setting is likely to be dependent on the number of resources available to pediatricians. Federal and state funding for POC testing in areas with high HCV prevalence might additionally help to identify cases and lead to better linkage to therapy, reducing risk for progression of disease, complications, and transmission.^[48] Additional HCV POC testing might reduce barriers to screening, including transportation and wait time for adolescent patients. Offering HCV testing as part of requests for sexually transmitted infection screening to this population or adolescents less than 18 years of age who are receiving other laboratory studies could also increase the size of screened population at little cost in terms of money or time.

6. Care in pregnancy

Current guidelines from the American Association for the Study of Liver Diseases do not recommend the use of direct-acting antivirals (DAAs) in pregnancy due to lack of safety data.^[49] There is a chance that later treatment, such as after the completion of organogenesis in the second trimester, might be an appropriate time for therapy, but this remains to be studied conclusively. Screening is universally recommended for pregnant women during each pregnancy. However, as with children, screening does not always result in linkage to care. A post hoc Medicaid claims analysis of 6 U.S. states (Delaware, Kentucky, Maine, North Carolina, Pennsylvania, and West Virginia) by Jarlenski and colleagues only found that 5.9% (95% CI, 4.9%–6.9%) of women who were diagnosed with HCV were provided medication within 6 months of delivery. Screening occurred in 70.3% of that cohort (23,780 mothers who had a diagnosis of opioid use disorder) between the years of 2016 and 2019. Of that group, HCV diagnosis occurred in 30.9%.^[50] In a Pittsburgh-based cohort of 791 women with opioid use disorder, 611 (77.2%) were screened for HCV, 369 (60.4%) tested positive, and a new infection was identified in 108 (29.3%). Of those who tested positive, 285 were referred to hepatology, but only 71 (24.9% of the subgroup) completed the visit, and only 6 (1.6%) received treatment.^[51]

Since there are difficulties linking patients in postpartum who are HCV positive with care, a phase I trial of 9 women who enrolled between 23 to 24 weeks gestation in Pittsburgh, Pennsylvania was conducted. In the study, women were provided 12 weeks of daily 90 mg ledipasvir plus 400 mg sofosbuvir. All 9 women achieved SVR12, and none of the infants (all term births) of these women tested positive for HCV (3 required care in the neonatal intensive care unit, but the longest stay was 12 d).^[52] The average birth weight was 3.29 kg.^[52] These infants otherwise had a routine, uncomplicated postnatal hospital course. Of a cohort of 100 women from Egypt with prior known HCV infection who had an unintended pregnancy while receiving a DAA, 9 patients completed the course against medical advice. Of this group, 7 had term deliveries and SVR12 (2 were unable to be reached for follow up).^[53] A current open label registry of pregnant women exposed to DAAs for HCV during pregnancy is ongoing in the United States (NCT05368974).

7. Co-infection of HBV and HCV in children

Co-infection with HBV can occur, but reports are limited. A study of 184 patients from across 3 hospitals in Cairo, Egypt in 2023 reported only 5 children with positive HCV antibodies; these children were not positive for other hepatitis viruses.^[54] El Khayat and colleagues reported no reactivation of HBV among a cohort of 115 adolescents aged 12 to 17 years with hepatitis B core antibody–positive status who also have chronic HCV and received daily sofosbuvir/ledipasvir for 12 weeks. Of the hepatitis B surface antigen–negative group, 98.2% achieved SVR12 compared to 96.7% of the hepatitis B surface antigen–positive group.^[55] Limited data on reinfection of HCV after initial clearance exists; however, data from adults (estimated at 3.76% based on pooled studies from Europe) suggest that co-infection with HIV would raise the risk for repeat infection.^[56]

8. Therapeutic options in children over 3 years of age

The advent of DAAs has changed the therapy landscape for children. Although approved in 2019, sofosbuvir and ribavirin are no longer preferred due to the availability (for patients aged 3 and older) and efficacy of pangenotypic DAA regimens. Now DAAs are available as pellets and tablets that can be consumed with or without food by children. Daily sofosbuvir/ledipasvir was approved for use in children 12 to 17 years with genotype 1, 4, 5, and 6 HCV without cirrhosis in 2017 after a 100-patient study showed 98% SVR12; the 2 patients who did not respond dropped out.^[57] Two follow up studies confirmed efficacy and safety in children between 3 to 11 years.^[58,59] Combination sofosbuvir/velpatasvir was provided to 216 children who were dosed according to their age group; the 3 to 5 years and <17 kg group was given 150 mg sofosbuvir/37.5 mg velpatasvir in oral granules, the 3 to 11 years and ≥17 kg group was given 200/50 mg low-dose tablet or oral granules, and the 12 to 17 years group was given 400/100 mg tablets, respectively. This study demonstrated only 2 cases of virologic failure, with an SVR12 of 83% among 3 to 5 year olds, 93% among 6 to 11 year olds, and 95% among 12 to 17 year olds. Only 1 serious adverse event (hallucination) was attributable to the medication.^[60] The combination was approved for children 6 years and older in 2020 and for children between 3 and 6 years of age in 2021.

The DORA phase 1 cohort showed 100% SVR12 (with no serious adverse events) in 47 adolescents (2 who had HIV) who received an adult dose of the pangenotypic combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 to 16 weeks.^[61] The second phase of DORA used weight-based dosing for glecaprevir/pibrentasvir, producing an SVR rate of 96%; this regimen was well tolerated. As with the phase 1 study, the phase 2 study reported no serious adverse events.^[62] This regimen was approved by the U.S. FDA in 2019 for children 12 to 17 years and extended to children as young as 3 years of age in 2021. The 3 regimens for non-cirrhotic patients are shown in Table 2 and the clinic trials listed in Table 3.^{[57,58,59,60,61,62 and 63]} Cirrhotic patients and those with prior DAA use but failure of treatment require longer second-round DAA regimens ranging from 16 to 24 weeks.

Table 2.

DAA therapy for interferon-experienced or treatment-naive children without cirrhosis or compensated cirrhosis.

Regimen	U.S. FDA approval	Genotypes	Brand name	Duration (weeks)	Daily dose
Sofosbuvir/ledipasvir	2017 (age 12–18 years)	1, 4, 5, and 6	Harvoni (Gilead, Foster City, California, USA)	12	<17 kg: 150 mg/33.75 mg
					17–35 kg: 200 mg/45 mg
					≥35 kg: 400 mg/90 mg
Sofosbuvir/velpatasvir	2020 (age 6+ years)2021 (age 3–6 years)	Pangenotypic	Epclusa (Gilead, Foster City, California, USA)	12	<17 kg: 100 mg/37.5 mg
					17–30 kg: 200 mg/50 mg
					≥30 kg: 400 mg/100 mg
Glecaprevir/pibrentasvir	2019 (age 12–18 years)2021 (age 3–12 years)	Pangenotypic	Mavyret (AbbVie, North Chicago, Illinois, USA)	8	<20 kg: 150 mg/60 mg
					≥20 to <30 kg: 200 mg/80 mg
					≥30 to <45 kg: 250 mg/100 mg
					≥45 kg or ≥12 years: 300 mg/120 mg

The ranges given in the Table are all greater than or equal to the lower limit value and less than the upper limit value. DAA: Direct-acting antiviral; U.S. FDA: United States Food and Drug Administration.

Table 3.

DAA clinical trials for treatment of HCV in children.

Year	Authors	Trial name	Trial design	Results
2017	Balistreri et al[57]	The Safety and Effectiveness of Ledipasvir/Sofosbuvir in Adolescents 12–17 Years Old With Hepatitis C Virus Genotype 1 Infection	• 100 children aged 12–17 years • 100/100 (100%) HCV GT 1 • 80% treatment naive • 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks	• 98/100 (98%) SVR at 12 weeks • 2/100 (2%) lost to follow up • 0% virologic failure
2018	Murray et al[58]	Safety and Efficacy of Ledipasvir-Sofosbuvir With or Without Ribavirin for Chronic HCV in Children Ages 6–11	• 92 children aged 6–11 years • 78% treatment naive • 88/92 (96%) HCV GT 1 • 45 mg ledipasvir and 200 mg sofosbuvir daily with or without ribavirin for 12 or 24 weeks	• 91/92 (98%) SVR at 12 weeks • 1/92 (1%) relapsed after receiving 12 weeks of treatment
2019	Jonas et al[61]	Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study	• 48 children aged 12–17 years • 79% HCV GT 1 • Also HCV GT 2, 3, and 4 • 77% treatment naive • 300 mg glecaprevir and 120 mg pibrentasvir once daily for 8–16 weeks (per adult indications)	• 47/48 (98%) SVR at 12 weeks • 1/48 (2%) lost to follow up • 0% virologic failure
2020a	Schwarz et al[59]	Ledipasvir-Sofosbuvir for 12 Weeks in Children 3 to <6 Years Old With Chronic HCV	• 34 children aged 3–6 years • 33/34 (97%) HCV GT 1 • 1/34 HCV GT 4 • 100% treatment naive • 33.75 mg ledipasvir and 150 mg sofosbuvir for weights <17 kg or 45 mg ledipasvir and 200 mg sofosbuvir for weights ≥17 kg	• 33/34 (97%) SVR at 12 weeks • 1/34 (3%) discontinued at day 5 due to taste • 0% virologic failure
2021a	Jonas et al[62]	Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study	• 80 children aged 3–12 years (cohorts: 3 to <6, 6 to <9, and 9 to <12 years) • 56/80 (70%) HCV GT 1 • Also GT 2, 3, 4, 5, and 6 • 78/80 (98%) treatment naive • 12 to <20 kg: 150 mg glecaprevir + 60 mg pibrentasvir • ≥20 to <30 kg: 200 mg glecaprevir + 80 mg pibrentasvir • ≥30 to <45 kg: 250 mg glecaprevir + 100 mg pibrentasvir	• 77/80 (96%) SVR at 12 weeks • 1/80 (1.25%) relapsed week 4 • 2/80 (2.5%) discontinued early due to non-response
2024	Jonas et al[60]	Sofosbuvir–Velpatasvir in Children 3–17 Years Old With HCV Infection	• 216 children aged 3–17 years (cohort: 3–5, 6–11, and 12–17 years) • 76% HCV GT 1 • Also GT 2, 3, 4, and 6 • 190/216 (88%) treatment naive • Sofosbuvir–velpatasvir 400/100 mg tablet (12–17 years), 200/50 mg (3–11 years and ≥17 kg), or 150/37.5 mg oral granules (3–5 years and <17 kg) for 12 weeks	• 97/102 (95%) SVR at 12 weeks in ages 12–7 years • 68/73 (93%) SVR at 12 weeks in ages 6–11 years • 34/41 (83%) SVR at 12 weeks in ages 3–5 years • 1/216 experienced virologic relapse after stopping study drug due to pregnancy

The ranges provided in the table are such that for the two clinical trials marked with “^a”, they are greater than or equal to the lower limit and less than the upper limit, whereas for the rest, they are greater than or equal to the lower limit and less than or equal to the upper limit. DAA: Direct-acting antiviral; GT: genotype; HCV: Hepatitis C virus; SVR: Sustained virologic response.

Data regarding longer term outcomes after DAA use are not as numerous for children as they are for adults with chronic HCV. In a retrospective cohort study of 245,596 adults with chronic HCV, DAA use was associated not only with increased SVR but with decreased rates of decompensation, HCC in compensated cirrhosis, diabetes, and chronic kidney disease.^[64] Pediatric data remain more limited. A recent publication on a cohort of 50 pediatric patients (aged 6–18 years) treated with 12 weeks of sofosbuvir and velpatasvir showed SVR12 with a brief decrease in weight z-score but continued SVR at 1 year with no change in height or weight z-scores from baseline.^[65] Additionally, a pediatric cohort of 24 individuals co-infected with HCV/HIV who cleared HCV with DAA therapy (between 2015 and 2017), who were subsequently followed for 5 years, showed reduction in alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase; they also showed increases in neutrophil and lymphocyte counts, neutrophil/lymphocyte and CD4/CD8 ratios, total cholesterol at 2 years, cholesterol/high-density lipoprotein (HDL) ratio at 4 years, triglycerides at 5 years, low-density lipoprotein over 5 years. Decreased HDL was shown across all patients.^[66] These studies suggest that DAAs may be associated with beneficial long term outcomes, but more specific assessments of hepatic outcomes would be needed. Observation of lipid trends with SVR would also be important in view of HCV’s hypolipidemic effects.

Hood and colleagues generated a stochastic model in 2024 to calculate the burden of acute and chronic HCV infections; they estimate that the burden should decline slightly by 2027 in the United States, given the availability of DAAs and younger age at time of initial screening.^[67] However, any decline would be dependent on pediatricians and family buy-in for testing and treating HCV.

9. Toward an HCV vaccine

Preventing HCV with a vaccine would be an important step forward in truly eliminating the virus as a health concern around the world. At present, HCV vaccine trials are not occurring in children. HCV viral vector vaccines designed to elicit robust T-cell responses have thus far been unsuccessful; the current theory is that a vaccine that promotes both cellular response as well as a humoral response with neutralizing antibodies against the E1E2 heterodimer may have a greater chance of success at preventing infection.^[68] A number of viral vector–based approaches deploying broader viral genotype coverage are under evaluation. In light of the recent unsuccessful randomized controlled trial of an HCV vaccine candidate that took many years to complete, the notion of use of a controlled human infection model has been proposed to accelerate testing of vaccine candidates.^{[69,70 and 71]}

10. Conclusion

HCV remains an active issue for children around the world since rapid progression can occur. It is critical to identify infected cases before advanced fibrosis and cirrhosis develop. Uniform data on prevalence by country, co-infections with HBV and HIV, and longer-term effects of the well-tolerated DAAs remain limited. MCTC as well as intravenous substance use represent the most likely cause for infection in pediatric cases. Earlier screening of exposed infants at 2 months of age offers an increased chance to link to care through the pediatrician’s office. Repeat HCV testing should occur prior to starting therapy with DAAs. DAAs represent an excellent treatment option for those aged 3 years and older; given their success and low side effect profile, movement of HCV treatment from the specialist to the primary care pediatrician’s office is distinctly possible. Although clearance of chronic HCV in all children is a goal, a truly protective HCV vaccine will be critical for the elimination of HCV infection.

Author Contributions

James Reed and Raymond Chung made significant contributions to the design of the article including drafting, revising, editing, and finalizing the manuscript. Both authors read and approved the final manuscript.

Conflicts of Interest

None.

Funding Statement

None.