Epidemiological characteristics and hepatitis C micro-elimination in children: experience of Tomsk Region

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Introduction

For many years parenteral hepatitis in children has been a global health problem and occupies a leading position among infectious diseases. The economic burden associated with the diagnosis and treatment of viral hepatitis C (HCV) in 2024 in the Russian Federation (RF) amounted to nearly 80 billion rubles [16]. Approximately 58 million people worldwide are infected with hepatitis C virus, including 11 million children aged 1 to 15 years, among whom viral replication is detected in 6 million [10, 16]. However, these statistics are continuously changing due to the lack of reliable data on the number of infected children in several countries [3, 5, 18]. According to data from the Centers for Disease Control and Prevention (CDC), Russia ranks 5th in the prevalence of parenteral hepatitis among children [17]. The low effectiveness of preventive measures against HCV infection, due to the absence of a vaccine and the often-asymptomatic course of infection, impedes timely and comprehensive control of the epidemic. Only 10% of infected individuals are aware of their disease, while the others pose a serious threat as sources of infection [3, 18]. In 2022, the incidence of HCV among children in the RF was 1.29 per 100 000 population.

In most developed countries, the primary route of infection in children is perinatal transmission [10]. According to global epidemiological surveillance, the average rate of vertical transmission of HCV in monoinfected pregnant women is approximately 5.8% [10]. About 33% of children acquire the infection during intrauterine development, while up to 50% of transmissions occur during the intranatal period. Several factors significantly influence the likelihood of vertical transmission of HCV [14].

One of the most significant factors is a high maternal viral load at delivery. The risk of transmission is directly proportional to the level of viral ribonucleic acid (RNA) in serum: at values above 10⁵ IU/mL, the probability of transmission increases, reaching its maximum at values above 10⁷ IU/mL. Elevated alanine aminotransferase (ALT) levels in the mother within 12 months before pregnancy or at delivery — reflecting active viral replication and greater liver damage — serve as an additional risk marker [17]. Other factors associated with viral transmission include obstetric history. Invasive procedures such as chorionic biopsy or fetal scalp electrode monitoring and a prolonged membrane rupture to delivery interval exceeding six hours have been reliably linked to a higher risk of neonatal infection. Similarly, complicated or prolonged labor increases maternal-fetal blood contact, facilitating vertical viral transmission [7]. Coinfection with human immunodeficiency virus type 1 (HIV-1) nearly doubles the transmission risk to 10.8% [3, 10, 18]. Contrary to earlier assumptions, caesarean delivery has not been proven to reduce the risk of vertical HCV transmission. Older children are most commonly infected through medical or non-medical procedures involving skin or mucosal injury, possible contamination, and blood transfusions, although such cases are rare [6, 10]. Intravenous drug use is another known risk factor.

The natural course of HCV in children differs markedly from that in adults, characterized by a higher rate of spontaneous clearance of HCV infection and usually slow progression. Observational studies report spontaneous elimination of HCV in 25% to 45% of children with perinatal HCV infection within the first two years of life without specific treatment. The likelihood of spontaneous clearance is higher in children with elevated ALT levels, possibly indicating a more robust immune response. The progression chronic hepatitis largely depends on the age at infection, in infants infected before one year of age, chronicity rates reach 90%, whereas at six years old, they range from 40% to 60% [5].

The aim of the study is to generalize epidemiological characteristics, features of the natural course, HCV outcomes, and to evaluate the effectiveness of DAA therapy in children with chronic viral hepatitis C in the Tomsk Region.

Materials and methods

A single-center, prospective observational study was conducted. An uncontrolled study without a control group to discover the effectiveness of a new treatment method for a certain sample of patients. For ethical reasons, the study does not include a control group, since the approved method of treatment is unacceptable for patients with hepatitis C. The study included all children under the age of 18 years with chronic HCV who were registered at medical institutions in Tomsk and the Tomsk Region. Sampling was not performed due to the use of a complete enumeration method.

The study was conducted in accordance with Declaration of Helsinki and the study protocol was approved by the Ethics Committee of Siberian State Medical University (Protocol No. 9476/1 dated 29/05/2023). Informed voluntary consent to participate in the study was obtained from the legal representatives and, where applicable, from the patients themselves. Personal data of patients were anonymized. All legal representatives and patients signed a voluntary informed consent to participate in the study.

The study included all children and adolescents with chronic HCV infection of both sexes, 3–18 years old or weighing > 12 kg (even if younger than 3 years) during the time period from May 2023 to 2025. Thirty-five children were monitored. The majority of the observed group were children aged 7–17 years, accounting for 58.3% (n = 21); patients under 1 year old constituted 2.7% (n = 1); those aged 1 to 3 years made up 14% (n = 5), and those aged 3 to 6 years were 25% (n = 9).

All children underwent a standardized examination in accordance with “Clinical guidelines for chronic viral hepatitis C in children (ID: 824). Diagnosis was confirmed by screening for HCV using enzyme immunoassay (EIA) and detection of HCV RNA by polymerase chain reaction (PCR). During follow-up, all patients underwent laboratory testing of indicators characterizing the main clinical-pathogenic hepatitis syndromes (ALT/AST activity, bilirubin, albumin, total protein, alkaline phosphatase), measurement of viral load, HCV genotype determination, and screening for hepatitis B virus (HBsAg) and HIV infection. Molecular genetic analysis by PCR was performed to determine HCV RNA (RealBest RNA HCV 1a/1b/2/3/4, Russia) levels and genotyping. HCV RNA levels below 50 IU/mL were considered below the system’s sensitivity limit and interpreted as indeterminate. Patients also underwent ultrasound examination (US) of the abdominal organs. The degree of liver fibrosis was assessed using Fibroscan (FibroScan^®Echosens, Paris, France) as well as APRI and FIB-4 tests. Degree of liver fibrosis was categorized into no fibrosis (F0), mild (F0–F1, F1), moderate (F1–2, F2) and marked (F3, F4).

The following data were collected from the patients’ files: demographic data (age and sex); risk factors of HCV acquisition (e.g. maternal HCV, intrafamilial cases, blood product transfusion, hospitalization, operation, chemotherapy); comorbidities; medication history (including previous HCV treatment and current therapy for comorbidities); and general, systemic and abdominal examination.

For treatment, a drug of DAAs of glecaprevir/pibrentasvir in the form of granules, covered, containing respectively 50 mg + 20 mg of drugs in 1 sachet. The drug was prescribed children with a body weight of 12–20 kg, 3 sachets/day, 20–30 kg — 4 sachets/day, 30–45 kg — 5 sachets/day; in children weighing more than 45 kg, the drug was prescribed single- multiples of 3 tablets/day containing, respectively, 100 mg + 40 mg drug substances each. Granules and patients took tablets with meals for 8 non-del.

Standard statistical methods were used to analyze the data. The parameters included in the analysis were age, sex, epidemiological and social history, clinical history, and laboratory and instrumental indicators. Statistical processing was performed using PSPP version 12.0 and Microsoft Excel for Windows 2011. Qualitative variables are expressed in absolute numbers with an indication of proportions (%) and calculation of the 95% confidence interval (CI) using the Clopper–Pearson method. Differences between groups on qualitative variables were assessed using Pearsons χ² (chi-square) test, with Yates’ correction applied when necessary. Quantitative variables are presented as median [Q1; Q3], where Me is the median, and Q1 and Q3 are the first and third quartiles, respectively (for non-parametric data). Correlation analysis was conducted using Spearman’s rank correlation coefficient. Differences were considered statistically significant at p < 0.05.

Results

According to the federal statistical surveillance form No. 65, “Information on Chronic Viral Hepatitis” of the Russian Federal State Statistics Service, also known as Rosstat (Order of Rosstat No. 354 dated 25.07.2023), and data from the federal register of viral hepatitis patients for 2023–2024, within the region and clinical settings from 2023 to the present, 36 children were registered. The prevalence rate of chronic hepatitis C was 16.6 per 100 000 children, or 0.017% of the infected pediatric population. Among the observed group, 32 children were registered in the clinic with chronic HCV at the end of 2023, and 4 children were newly diagnosed in 2024. Analysis of gender distribution showed a predominance of male children compared to females (95%CI: 46.5–78.9%) (Table 1). The observed difference from a 1:1 sex ratio was not statistically significant (exact binomial test, p = 0.16).

 

Table 1. Characteristics of the study sample

Characteristic	Absolute number, n = 35 (%)	95%CI (Clopper–Pearson)	p value
Gender
male	22 (63.9)	46.2–79.2%	p = 0.16
female	13 (36.1)	20.8–53.8%
Transmission
vertical	34 (94.4)	81.3–99.3%	p < 0.0001
haemocontact	2 (5.6)	0.7–18.7%
Biochemical parameters
ALT elevated	4 (11.1)	3.1–26.1%	p = 0.10 -
Bilirubin elevated	0 (0)	0.0–9.7%
Genotype
1	12 (48)	27.8–68.7%	p = 0.02
2	2 (8)	1.0–26.0%
3	11 (44)	24.4–65.1%
Not defined	11 (33.3)	16.3–48.1%
HCV RNA load
≤ 800 000 IU/L	20 (55.6)	49.2–84.7%	p = 0.06
≥ 800 000 IU/L	9 (25)	15.3–50.8%
No data	7 (19.4)	8.2–36.0%
Fibroscan (METAVIR score)
F0 (≤ 5,8 kPа)	8 (53.3)	26.6–78.7%
F1 (от 5,9 до 7,2 kPа)	4 (26.7)	7.8–55.1%
F2 (от 7,3 до 9,5 kPа)	2 (13.3)	1.7–40.5%
F3 (от 9,6 до 12,5 kPа)	1 (6.7)	0.2–31.9%
F4 (> 12,5 kPа)	0	0.0–21.8%
No data	21 (58.3)	40.8–74.5%	0.02
HIV/HCV co-infections	3 (8.3)	1.8–22.5%	p = 0.03
Treatment naive for DAAs	0

 

HIV/HCV co-infection infection was detected in three children, all of whom acquired the infection vertically from their mothers 8.3%, 95%CI: 1.8–22.5%); no other parenteral hepatitis cases were identified. Comorbid conditions were diagnosed in 4 out of 36 children (11.1%, 95%CI: 3.1–26.1%), including single cases of diabetes mellitus, nephrotic syndrome with minor glomerular changes, bronchial asthma, and cerebral palsy (each 2.8%, 95%CI: 0.07–14.5%). Although each condition alone did not reach statistical significance (p = 0.08, indicating a trend), the presence of any comorbid condition as a composite measure was significant (p = 0.02).

Epidemiological history revealed a vertical route of HCV transmission in 94.4% of children (94.4%, 95%CI: 81.3–99.3%) born to HCV-infected mothers. Two patients reported medical procedures involving skin or mucous membrane injury as possible modes of infection; however, the validity of these reports could not be confirmed (5.6%, 95%CI: 0.7–18.7%). The predominance of the vertical route was highly statistically significant (exact binomial test, p < 0.0001).

At the time of observation, HCV infection was asymptomatic in all patients; cholestasis syndrome, hepatic signs, and hemorrhagic syndrome manifestations were absent. At diagnosis, one child presented with a manifest form of HCV accompanied by jaundice, while the other patients had no specific complaints.

HCV RNA load data were available for 29 out of 36 children (80.6%). Among these, 20 patients (69.0%, 95%CI: 49.2–84.7%) had a low viral load (≤ 800 000 IU/L), while 9 patients (31.0%, 95%CI: 15.3–50.8%) had a high viral load (≥ 800 000 IU/L). The predominance of low viral load did not reach statistical significance when compared to an expected equal distribution (exact binomial test, p = 0.06). The association between HCV genotype and viral load among the 25 children with known genotypes was found no significant (p = 1.00). Correlation analysis revealed a positive association between viremia level and disease duration (r = 0.46, p < 0.05). Genotype distribution was determined in 25 out of 36 children (69.4%). The most prevalent genotypes were genotype 1 (n = 12, 48%) and genotype 3 (n = 11, 44%), while genotype 2 was rare (n = 2, 8%). The analysis by Fisher test confirmed a statistically significant difference in genotype frequencies (p = 0.02), indicating a true predominance of genotypes 1 and 3 in this pediatric cohort. No cases of mixed genotype infection were identified. In 11 patients, genotyping was not performed due to the use of pangenotypic antiviral drugs in therapy.

Liver stiffness measurement by Fibroscan was available for 15 out of 36 children (41.7%). Among these, the majority had no significant fibrosis: 8 children (53.3%) were classified as F0 (METAVIR), and 4 (26.7%) as F1. Clinically significant fibrosis (F2 or higher) was observed in 3 children (20.0%), including two with F2 (13.3%) and one with F3 (6.7%). No children presented with cirrhosis (F4). Due to the small sample size, exact 95% confidence intervals (CIs) were calculated using the Clopper–Pearson method. The proportion of children with significant fibrosis (F2–F3) was 20.0% (95%CI: 4.3–48.1%). Analysis of the liver elastography data revealed a significant positive correlation between the severity of liver fibrosis and both disease duration (r = 0.6, p < 0.05) and patient age (r = 0.58, p < 0.05).

HCV was first diagnosed in 94.4% of children (n = 34/36, 95%CI: 81.3–98.9%) aged 0 to 3 years. The median duration of the disease was 5 [3; 8] years, and four children were diagnosed within one year (Table 2).

 

Table 2. Initial characteristics of patients

Characteristic	Me [Q1; Q3]
Age at diagnosis, years	1 [0.4; 3]
Duration of disease, years	5 [3; 8]
Average age at initiation of antiviral therapy, years	8 [5; 12]
Biochemical parameters
ALT, U/L	33 [19.66; 67]
АSТ, U/L	41 [25; 66]
Total bilirubin, mmol/L	7.62 [5.285; 11,7]
Albumin, g/L	46 [43.1; 48.2]
Coagulation system indicators
Platelets, 109 /L	289 [238; 316]
Fibrinogen, g/L	2.205 [1.9; 2,7]
Prothrombin index (PTI), %	96 [94; 100.6]
Activated partial thromboplastin time (aPTT), sec	33 [30; 36.8]
Prothrombin time, sec	16.25 [15; 17]
HCV RNA, copies/mL	308 000 [90 100; 1 700 000]
Calculated fibrosis indices
APRI index	0.28 [0.22; 0.36]
FIB-4 index	0.19 [0.12; 0.24]

Note. ALT — Alanine aminotransferase, AST — Aspartate aminotransferase, PTI — prothrombin index, aPTT — Activated partial thromboplastin time, HCV — hepatitis С virus, RNA –Ribonucleic acid, Me — median, Q1 — first quartile, Q3 — third quartile.

 

In the study of biochemical indicators, it was found that in most cases (88.9%) the activity level of alanine aminotransferase (ALT) did not exceed the upper limit of the age-specific reference range: four patients demonstrated mildly increased cytolytic activity within 5 times the age norm. Hypertransaminasemia was diagnosed in one child co-infected with HIV and in another child with infantile cerebral paralysis as a comorbid condition.

All patients underwent ultrasound examination of the abdominal organs. Abdominal ultrasound was performed in all 36 children. Diffuse liver changes were observed in 6 patients (16.6%, 95%CI: 6.4–32.8%), hepatomegaly in 7 patients (19.4%, 95%CI: 8.2–36.0%), and splenomegaly in 1 patient (2.8%, 95%CI: 0.07–14.5%). No fibrotic or cirrhotic changes were detected by ultrasound in any patient (0%, 95%CI: 0.0–9.7%).

Anamnesis revealed that all children had received antiviral therapy with interferon alfa-2b administered rectally in courses of varying duration, without achieving viral remission. One patient showed spontaneous viral elimination over a 2-year retrospective observation. None of the patients in the study group had experience with pegylated interferon or ribavirin.

All children with HCV older than 3 years of age, regardless of genotype, received an 8-week course of glecaprevir/pibrentasvir at appropriate age-based dosages. The median age at therapy initiation was 8 [5; 12] years. No serious drug-related adverse effects requiring therapy discontinuation were observed during treatment. Virological response was monitored in all children at 12 weeks after treatment completion according to regulations. All patients who received glecaprevir/pibrentasvir therapy achieved undetectable HCV RNA levels and showed no laboratory evidence of cytolysis syndrome post-therapy, indicating a sustained virological response.

Discussion

Study limitations. When interpreting the results obtained, several methodological limitations that may affect the degree of reliability and the generalizability of the conclusions must be considered.

The studied patient cohort is characterized by a limited sample size (n = 36), which precludes stratification of patients by key variables (age, sex, comorbid conditions) for multivariate analysis and increases the risk of statistical errors.

The absence of a control group limits the ability to assess the specificity of the identified elastographic and serum markers and to determine the extent to which changes in liver stiffness are attributable to the course of chronic hepatitis C (CHC) rather than to other underlying conditions. The inclusion of a healthy control group or a comparison group (e.g., patients with non-alcoholic fatty liver disease without diabetes mellitus) in the study design at this stage was deemed ethically and organizationally challenging, as it would not align with the principles of bioethics.

Patient enrollment was conducted exclusively at medical institutions in the Tomsk Region. The obtained results reflect the situation in a specific region and limit the possibility of extrapolating the findings to other populations.

The cross-sectional study design allows only for the establishment of associations between the studied factors and liver fibrosis at the time of inclusion, but it does not allow for tracking the dynamics of the process. The absence of a prospective follow-up phase precludes the assessment of fibrosis progression rates, the frequency of regression during therapy, or the incidence of adverse outcomes (cirrhosis, hepatocellular carcinoma) in the studied cohort.

The combination of the aforementioned factors (small sample size, incomplete elastography data, and lack of a control group) determines the preliminary nature of the conclusions. The absence of a control group and the limited geographic scope prevent the identified prevalence and degree of fibrosis from being considered definitive population parameters. In this regard, the presented results should be viewed as a hypothesis requiring verification in prospective, controlled studies with stricter inclusion criteria.

The results of the study are consistent with existing literature on the course of HCV infection in children and adolescents [2, 13, 14]. The age distribution was predominantly represented by school-age children. Among HCV patients, the average duration of disease was 5 years. The presence of comorbid conditions in this cohort suggests that children with chronic hepatitis C may be at an increased risk for concomitant diseases, highlighting the need for comprehensive clinical evaluation. The primary route of HCV transmission in children is vertical. The disease course is typically latent, accompanied by minimal laboratory changes, yet characterized by replacement of healthy liver tissue with connective tissue. Liver elastography revealed varying degrees of fibrosis in the absence of clinical symptoms. However, advanced liver disease was present in a subset of this pediatric cohort, despite the overall mild profile. Notably, while no fibrosis was detected on ultrasound, subsequent elastography revealed significant fibrosis (F2–F3) in three children (see above), highlighting the limited sensitivity of conventional ultrasound for detecting early-stage liver fibrosis. The development of liver fibrosis is associated with disease duration and increases the risk of life-threatening complications. An inactive inflammatory process in liver tissue corresponds with a low viral load. The genotype distribution in children mirrors that observed in adults [2].

Until recently, a major obstacle to eliminating HCV in children was the absence of antiviral drugs with proven clinical efficacy and pediatric approval. However, the introduction of direct-acting antiviral (DAA) agents marked significant progress in HCV therapy, fundamentally changing the management approach. The incorporation of DAAs into clinical practice has opened new opportunities for effective HCV elimination in children, demonstrating high rates of sustained virological response and improved safety profiles compared to interferon-based regimens [18]. This breakthrough has increased access to therapy and improved prognosis for pediatric patients with HCV.

The most significant modifications to the pediatric HCV treatment protocol were proposed by the professional communities of ESPGHAN and WHO in 2018. Their recommendations advocated discontinuation of interferon-based regimens due to low efficacy and significant adverse effects, advising delayed treatment initiation with DAAs until children reach 12 years of age. In 2019, the first DAA regimens with high safety and efficacy were approved in the Russian Federation for treating chronic HCV of all genotypes in patients aged 12 to 17 years, and in 2022, approval was extended to children over 3 years old. A major breakthrough in HCV treatment in the Russian Federation, enabling microelimination of HCV among the pediatric population, was the decision by the expert council of the Foundation “Circle of Kindness” dated 02.03.2023. According to Protocol No. 15, HCV was included in the list of severe, life-threatening, and chronic diseases, including rare (orphan) diseases. This document facilitated rapid access to DAAs for children suffering from HCV. The results of the present study confirmed the high effectiveness of DAA use in children aged 3 to 17 years. A strength of our study is the inclusion of children with comorbid conditions such as viral coinfection (human immunodeficiency virus). Over two years, the Foundation “Circle of Kindness” supported a microelimination program for pediatric HCV in the Tomsk Region. The conducted antiviral therapy gives a stable virological response in 100% of cases and contributes to the normalization of biochemical parameters, as well as the regression of fibrosis in all children who received glecaprevir+pibrentasvir for 8 weeks [4, 21]. Our study demonstrated that the pangenotypic DAAs therapy achieved comparable rates to those observed with earlier studies (100%) [1, 9, 12, 20]. Short regimens, in our opinion, contribute to increased adherence to treatment. Although our study did not evaluate other regimens, future studies are needed to evaluate their efficacy in real pediatric populations.

Our findings affirm the safety and efficacy of the pangenotypic DAAs in these special pediatric subgroups. This supports the micro-elimination approach advocated by the World Health Organization, targeting high-risk HCV populations and those exposed via vertical transmission. Furthermore, our study highlights the role played by the Russian government in subsidizing the prices of DAAs, facilitating their widespread availability to both adult and pediatric populations. The financial model adopted by Russian national HCV elimination program supports the feasibility and sustainability in other countries. Since vaccination against HCV has not yet been developed, the most effective method for the further spread of this infection is the early detection and treatment of children and adolescents suffering from CHC using direct antiviral agents. In the near future, children may become the first category of patients in which the elimination of HCV infection in Russia has been achieved.

Conclusion

The pediatric HCV cohort was characterized by predominantly school-age children with vertically acquired infection (mean duration 5 years) and a high prevalence of comorbid conditions. The disease followed a latent course with minimal laboratory changes but notable fibrotic progression, underscoring the need for comprehensive clinical evaluation beyond standard liver tests.

Conventional ultrasound demonstrated limited sensitivity for detecting early-stage liver fibrosis, whereas elastography revealed significant fibrosis (F2–F3) even in asymptomatic children. This confirms that elastography is essential for accurate staging and should be routinely integrated into pediatric HCV assessment.

The inclusion of HCV in the “Circle of Kindness” Foundation’s list of severe diseases (2023) enabled rapid, state-subsidized access to DAAs for children. The Tomsk Region experience exemplifies how federal policy support can be effectively translated into regional microelimination programs.

Pangenotypic DAA therapy (glecaprevir/pibrentasvir) achieved 100% sustained virological response, including in children with HIV coinfection, confirming its safety and efficacy in vulnerable subgroups. Short 8-week regimens further support treatment adherence.

Scaling the Tomsk model to other regions — through replication of the funding mechanism and regional screening programs — could position the pediatric population as the first in Russia to achieve HCV elimination.

About the authors

Yuliya А. Ermolaeva

Siberian State Medical University; Novosibirsk Scientific Research Institute of Tuberculosis

Author for correspondence.
Email: euassmu@yandex.ru

PhD (Medicine), Associate Professor, Department of Pediatrics with Endocrinology Course, Siberian State Medical University of the Ministry of Health of the Russian Federation; Deputy Director for Scientific Work, Novosibirsk Scientific Research Institute of Tuberculosis

Russian Federation, Tomsk; Novosibirsk

References

Supplementary files