Chronic viral hepatitis C (CVHC) in children: clinical guidelines

List of Abbreviations

ALT - alanine aminotransferase

Anti-core, Anti-HCV-core IgG — antibodies to the core protein class G of hepatitis C virus

Anti-HCV IgM — immunoglobulin M antibodies to hepatitis C virus antigens Anti-HCV

Anti-HCV-total — antibodies to hepatitis C virus (total)

Anti-NS3, -NS4, -NS5 — Anti-HCV-NS3, Anti-HCV-NS4, Anti-HCV-NS5 — antibodies to non-structural proteins NS3, NS4, NS5 NS2, NS3, NS4a, NS4b, NS5a, NS5b

AST — aspartate aminotransferase

HBV — hepatitis B virus

HCV — hepatitis C virus

ULN — upper limit of normal

HIV - human immunodeficiency virus

VL — Viral Load — quantitative content of viral nucleic acid

in 1 µl of blood/plasma (copies/µl, IU/µl/IU/ml)

GGT — gamma-glutamyl transferase

GT — virus genotype (GT HCV)

HCC – hepatocellular carcinoma

CT — computed tomography

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

MRI — magnetic resonance imaging

INR – international normalized ratio

LBP – liver puncture biopsy

AVT – antiviral therapy

DAAs – direct-acting antivirals

PT - prothrombin index

RCT — randomized controlled trial

RNA - ribonucleic acid

RF - Russian Federation

ESR – erythrocyte sedimentation rate

Ultrasound — ultrasound examination

EGD – esophagogastroduodenoscopy

Federal Law

CHC - chronic viral hepatitis C

CLIA – chemiluminescent immunoassay

LC – liver cirrhosis

CTLs – cytotoxic lymphocytes

ALP - alkaline phosphatase

HAV – hepatitis A virus

HBV - hepatitis B virus

HCV – hepatitis C virus

IgG - immunoglobulin G

IgM - immunoglobulin M

IL28B – interleukin 28B

RBV – ribavirin**

RT-PCR – real-time polymerase chain reaction allowing viral load determination by amplification.

Terms and Definitions

Viral load (VL) – the amount of viral RNA in the blood, IU/mL or copies/mL. Hepatocellular carcinoma – a malignant liver neoplasm. It is one of the unfavorable outcomes of chronic hepatitis C. In most cases, it develops against the background of liver cirrhosis.

Coinfection – infection with two or more infectious agents

Pangenotypic therapy – a regimen of antiviral therapy with agents effective against all HCV genotypes

Relapse of CHCV infection – the appearance of HCV RNA (VL) in the blood after the completion of a successful course of therapy (achieving an undetectable HCV RNA level at the end of treatment).

Sustained virological response – an undetectable level of HCV RNA (VL) in the blood 12 or 24 weeks after the end of therapy (depending on the treatment regimen).

APRI – a non-invasive method for diagnosing liver fibrosis, a calculated index based on the AST-to-platelet ratio.

FIB-4 – a non-invasive method for diagnosing liver fibrosis, a calculated index based on patient age, ALT, AST, platelet count, and INR.

Metavir – an international scoring system for liver fibrosis (F0/FII/FIII/FIV) and the degree of inflammation in liver tissue (A0–AIII). Used in both histological examination of liver tissue and non-invasive methods of fibrosis diagnostics.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic hepatitis C (CHCV) is an infectious disease caused by the RNA-containing hepatitis C virus (HCV), with parenteral and blood-borne transmission mechanisms and natural and artificial routes of transmission. The diagnosis is established when viral persistence lasts for at least 6 months. The disease has a prolonged course. During the first 10–18 years, it generally proceeds with scarce clinical symptoms. In clinically manifest cases, it presents with mild symptoms of liver damage (rarely with jaundice) and transiently elevated transaminase activity. In late stages, it is associated with the development of liver cirrhosis and/or hepatocellular carcinoma.

CHCV is a form of HCV infection, the outcome of the acute phase of the disease that occurs in the majority of children via vertical transmission and remains paucisymptomatic almost until the puberty period.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Etiology. Hepatitis C virus (HCV) was discovered in 1989 [1]. For the discovery and study of this virus, H. J. Alter (USA), M. Houghton (UK), and C. M. Rice (USA) were awarded the Nobel Prize in 2020. HCV contains single-stranded RNA and belongs to the family Flaviviridae, representing the third, independent genus Hepacivirus therein. The HCV genome encodes structural and non-structural proteins. Structural proteins include the C-core protein and envelope glycoproteins E1 and E2, while non-structural proteins include a complex of proteins with specific enzymatic activity (NS2-3 through NS5: NS2, NS3, NS4a, NS4b, NS5a, NS5b). Antibodies are produced against each of the structural and non-structural viral proteins, which lack virus-neutralizing properties. A characteristic feature of HCV is its ability to rapidly substitute nucleotides, leading to the formation of a large number of genotypes, subtypes, and mutant strains [2]. There are 8 viral genotypes. Genotypes are further subdivided into subtypes with a nucleotide sequence divergence of more than 15%. To date, more than 90 confirmed HCV subtypes have been described, and potentially more genotypes and subtypes will be identified. Furthermore, in infected patients, the virus exists as a set of virions containing slightly altered but closely related genomes, so-called quasispecies [3]. Such variability of the viral genome leads to changes in the structure of antigenic determinants that determine the production of specific antibodies unable to eliminate the virus from the body and hindering the development of an effective vaccine against hepatitis C. Until recently, HCV was classified into seven distinct genotypes differing in nucleotide sequence by more than 30% [4]. A new HCV genotype 8, which forms a separate phylogenetic group from previously described sequences, was recently identified in four epidemiologically unrelated patients from India [5]. In the Russian Federation (RF), genotypes 1, 2, 3 and subtypes 1b and 3a are most common. Other viral genotypes are practically not encountered in the territory of the RF [6]. HCV genotyping by PCR with determination of the viral genotype and subtype is recommended in children with CHCV for the differential diagnosis of potential relapse and reinfection.

HCV, compared to HAV and HBV viruses, is unstable in the external environment and against physical and chemical factors. It is sensitive to chloroform, formalin, UV radiation, is inactivated at 60°C within 30 minutes, and upon boiling (100°C) – within 2 minutes [2, 7].

Pathogenesis. The virus enters the body of a susceptible person along with infected blood. An essential condition for the development of the infectious process is the penetration of HCV into hepatocytes, where its replication and interaction with the immune system take place. The interaction of the organism with HCV is an immunopathological process. Hepatocyte damage is driven by the activation of cellular and humoral immune responses ultimately aimed at eliminating HCV. Cellular cytotoxic reactions mediated by various classes of effector cells work towards HCV elimination. Disruption of the Th1/Th2 cytokine production balance plays a crucial role in the development of various forms of HCV infection. Enhanced production of IL-4 and IL-10 inhibits T-lymphocyte function, suppresses the production of IFN-γ and IL-2, and contributes to the chronic course of the disease [8,9].

Target cells for HCV are not only hepatocytes, but also immunocompetent peripheral blood cells — PBMC/WBC (Peripheral Blood Mononuclear Cells I White Blood cells). To date, two specific lymphotropic strains of the hepatitis C virus have been verified (Ly-HCV and SB-HCV). When a susceptible organism is infected with one of these lymphotropic strains, the pathological (inflammatory) process in the liver is minimal, since the primary "blow" of the HCV virus is dealt not to liver hepatocytes, but to peripheral blood immune cells (PBMC/WBC), with all the ensuing adverse clinical consequences (autoimmune, lymphoproliferative, etc.) [10]. HCV is capable of suppressing CD4+ activation by disrupting the interaction between antigen-presenting cells and T-lymphocytes. The ability of the virus to replicate in immune-privileged sites (immune system cells, brain tissues) makes it inaccessible to CTLs. The humoral response in HCV is less pronounced.

In addition to the direct cytopathic effect, the leading mechanisms of liver damage are immune cytolysis, apoptosis, and an autoimmune mechanism, which is associated with a high frequency of extrahepatic manifestations in HCV infection (vasculitis, glomerulonephritis, peripheral neuropathy, polyarteritis nodosa, arthritis, Sjögren's syndrome). Immune cell and immune complex processes underlie the genesis of these diseases. Therefore, HCV infection can be considered a multisystem disease. However, in childhood, CHCV rarely shows polyorgan involvement. Multisystem involvement in children with CHCV is extremely rare and incomparable in frequency to that seen in CHCB (Gianotti-Crosti syndrome, glomerulopathies, vasculitis) [2,10,11].

An important role is also assigned to immunogenetic factors. This is evidenced by differences in the detection rate of CHCV among various ethnic groups living in the same territory, and the fact that a favorable outcome of acute HCV is more frequently recorded in patients with HLA class II genotype [4,11].

In utero infection during the first 12 weeks (mainly 15–75 days) with a high viral load and fetoplacental complex pathology (chronic intrauterine fetal hypoxia, intrauterine growth restriction, placentitis) may lead to early termination of pregnancy. With continued maternal infection and a high viral load between 75 and 180 days of the intrauterine period, early fetopathies may develop, leading to late pregnancy termination or developmental anomalies of the liver and biliary tract. With continued maternal infection and a high viral load after 180 days of the intrauterine period, fetal HCV hepatitis may develop, or—which is extremely rare in the absence of comorbid pathology—fetal HCV liver cirrhosis [2, 11].

1.3 Epidemiology of the Disease or Condition

The source of infection includes individuals infected with HCV who are in the incubation period (14–180 days), as well as patients with hepatitis C virus (HCV) infection, including those with asymptomatic acute or chronic forms of HCV. The mechanism of infection is parenteral and blood-borne, which is realized through natural and artificial transmission routes [2, 7, 12].

Among natural transmission routes, the vertical route is of primary importance in childhood—involving transplacental, intranatal, and postnatal infection of the child from the mother—as well as the horizontal route, which in some cases occurs in adolescents through sexual contact [2, 7, 11, 12]. The artificial (blood-borne) route of infection, in which chronic hepatitis C (CHC) develops as a healthcare-associated infection (HAI)—post-transfusion, catheter-associated, post-injection, and associated with other invasive procedures—can occur in children of any age.

The main medical procedures associated with a risk of HCV infection include blood or blood component transfusion, organ or tissue transplantation, hemodialysis procedures (high risk), and various parenteral interventions [13]. In Western Europe and the USA, HCV accounts for 75–95% of post-transfusion hepatitis cases. Among patients receiving blood infusions as part of complex therapy, the highest HCV infection rate is registered in patients with hemophilia—at 45–80% [14]. Children with oncohematological diseases are also a risk group. However, currently, following the introduction of routine screening for HCV infection in blood transfusion services, the frequency of this transmission route has sharply decreased and does not exceed 2–3% [15, 16].

In adolescents, artificial transmission routes may be of epidemiological significance, realized through non-medical and medical procedures accompanied by damage to the skin or mucous membranes, as well as procedures associated with the risk of such damage. Non-medical procedures include: intravenous drug use (highest risk), paramedical interventions—such as tattooing, body piercing, cosmetic procedures, manicures, pedicures, and other procedures using HCV-contaminated instruments, and sometimes specific ritual practices among certain ethnic groups. In addition, adolescents are at risk of infection as a result of unprotected sexual practices, especially among men who have sex with men [2, 11,

12].

Much attention from researchers is directed toward studying the realization of natural HCV transmission routes. The main transmission factor is blood or its components, and to a lesser extent, other human biological fluids (semen, vaginal secretions, tears, saliva, etc.). It has been established that the infectious dose of HCV is 2–3 orders of magnitude higher than that of HBV; accordingly, the probability of infection upon contact is lower. However, most authors indicate the possibility of HCV transmission through hetero- and homosexual sexual contacts—the risk of infection among regular heterosexual partners, one of whom has CHC, is 1.5% (in the absence of other risk factors) [2, 6, 7, 11, 12]. Nevertheless, in childhood these routes are practically insignificant. These epidemiological factors must be considered when assessing the epidemiological situation regarding HCV infection within a family, especially in cases where an infected mother is caring for a child [17]. To date, sufficient information has also been accumulated on HCV transmission through household contact within a family—hidden blood-borne infection via microtraumas of the outer integument. According to WHO data, the probability of household transmission can reach 7% [14].

Transmission of the virus from an infected mother to her child is possible during pregnancy and childbirth (risk 1–5%). The probability of newborn infection increases significantly at high HCV concentrations in maternal blood serum (7–12%), as well as in the presence of HIV co-infection (14–16%) [11, 12, 18]. The frequency of HCV transmission increases with prolonged labor, amniocentesis, fetal scalp blood monitoring, and a prolonged rupture of membranes. Recent studies have shown that breastfeeding does not affect the rate of infection in children [19, 20, 21].

In Russia, acute HCV in children is detected rarely, accounting for 0.55 cases per 100,000 child population, and among all acute hepatitis cases, the proportion of children with acute HCV does not exceed 1–2% [22, 23].

In 90–95% of cases, the disease in early childhood proceeds in an anicteric, subclinical, and inapparent form with a high rate of chronicity—ranging from 40–56% to 81% or more [2, 18–20].

Currently, CHC predominates in the etiological structure of newly registered cases of chronic viral hepatitis. Between 1999 and 2017, its proportion increased from 54.8% to 77.97%. The number of registered cases and the incidence rate of CHC in the Russian Federation in 2019 amounted to 45,262 (30.82 per 100,000 population); among children aged 0–17 years

– 381 (1.31 per 100,000 pop.), aged 0–14 years – 268 (1.04 per 100,000 pop.) [22, 23].

1.4 Features of Coding the Disease or Condition

B18.2 - Chronic viral hepatitis C

Along with the ICD-10 classification, it is mandatory to use a clinical classification focused on the dynamics of the disease course and treatment monitoring. The use of these classifications in clinical practice allows for formulating both a primary (preliminary) diagnosis—at the initial stage of patient management—and a clinical diagnosis (laboratory- and instrumentally verified), which is established within 10 days of observation, indicating the genotype (HCV GT) and the degree of liver fibrosis (disease stage), and in the case of liver cirrhosis development, class F4 according to the Child-Pugh scale. In the final (definitive clinical) diagnosis, which is established upon discharge of the child from the hospital and when filling out medical record form 066/u (discharge summary), the ICD-10 code must be indicated at the beginning of the diagnosis.

1.5 Classification of the disease or condition

Nosological form - CHC indicating the HCV verification method (optionally indicating the detection method and equipment): Chronic viral hepatitis C (blood EIA - anti-HCV IgM positive, anti-HCV IgG positive, blood PCR - HCV RNA positive).

Stage of the disease (severity of liver fibrosis according to the METAVIR scale) - indicating the rating scale, determination method, and preferably equipment: METAVIR - FibroScan - EchoSens, France):

F0 - no fibrosis;

F1 - mild fibrosis;

F2 - moderate fibrosis;

F3 - severe fibrosis;

F4 - liver cirrhosis.

1.1.3.    HCV genotype - GT HCV:

GT 1, Genotype 1

GT 1a, Genotype 1a

GT 1b, Genotype 1b

GT 2, Genotype 2

GT 3, Genotype 3

GT 4, Genotype 4

GT 5, Genotype 5

GT 6, Genotype 6

GT 7, Genotype 7

GT 8, Genotype 8

Grade of CHCV activity - severity of the disease course. In the absence of percutaneous liver biopsy, which provides an assessment based on the histological examination of liver tissue (by the severity of hepatocellular necrosis - Knodell index), the grade of activity is roughly estimated by the degree of ALT and AST elevation as a multiple of the upper limit of normal (ULN): minimal - 1.5–2 times the upper limit of normal; low - 2–5 times; moderate - 5–10 times; marked (high) - more than 10 times the ULN.

Examples of diagnosis formulation:

Preliminary diagnosis (newly diagnosed disease - case suspected of CHCV / probable case of CHCV): Chronic viral hepatitis C (blood ELISA - anti-HCV IgM positive, anti-HCV IgG positive);

Clinical diagnosis (confirmed case of CHCV): Chronic viral hepatitis C (blood ELISA - anti-HCV IgG positive, blood PCR - HCV RNA positive), genotype 3, fibrosis stage F1.

Final (definitive clinical) diagnosis of CHCV: B18.2

Chronic viral hepatitis (blood ELISA - anti-HCV IgG positive, blood PCR - HCV RNA positive), genotype 1a, fibrosis stage F4, Child-Pugh class B .

1.6 Clinical presentation of the disease or condition

Chronic HCV infection in children is characterized by viremia and scanty clinical symptoms. A careful medical history in most adolescent patients, less frequently in school-age children, and rarely in preschoolers, usually reveals: asthenovegetative syndrome (increased fatigue, especially after physical education classes or sports sections; decreased and/or selective appetite, intermittent pain in the right upper quadrant associated with dietary indiscretions or physical exertion). Hepatomegaly—the main symptom of the disease—may be its sole clinical manifestation. Palpation of the liver reveals slight tenderness and increased consistency. Splenomegaly is less consistent and is more often combined with hemorrhagic syndrome (cutaneous petechial hemorrhages and thrombocytopenia). Occasionally, older children and adolescents may show signs of chronic coagulopathy (impaired synthesis of hepatic clotting factors, primarily the prothrombin complex) manifesting as mild bruising and spontaneous epistaxis without signs of nasal septal vasopathy or arterial hypertension [11, 19-20, 24].

Extrahepatic manifestations of HCV infection, which are potentially severe in adults, are rare in children, with the exception of subclinical hypothyroidism and autoimmune thyroiditis, which occur in an average of 11% and 6% of cases, respectively [10, 26].

Clinical symptoms of the disease may be entirely absent. In biochemical blood tests, transaminase activity ranges from normal to moderate values, exceeding the upper limit of normal (ULN) by 5–6 times. However, in most cases, the level of hyperfermentemia is minimal—ALT and AST levels do not exceed 1.5–2 times the ULN and tend to fluctuate in a wave-like manner. Pigment metabolism and the protein-synthetic function of the liver are generally unimpaired. Blood tests detect total anti-HCV IgG (antibodies to structural and non-structural viral proteins: core, NS3, NS4, NS5) and HCV RNA [11, 19–20, 24–25].

The mildly symptomatic course of chronic HCV infection in children infected at an early age can persist for a long time, extending into adulthood. However, normal ALT and AST activity does not rule out ongoing liver changes, because the activity (severity) of chronic HCV infection is assessed not only by the severity of clinical manifestations and the fold increase in ALT relative to the ULN, but also by the degree of liver fibrosis. In advanced stages (F3 and F4 according to the METAVIR scale, see Appendix G), long-standing fibrosis is the primary cause of severe complications and an unfavorable disease outcome.

Most children maintain an almost normal liver histology many years after infection [27, 28]. However, progressive organ damage was identified in some children as early as 1 year post-infection [24, 28]. The risk of cirrhosis in children with chronic HCV infection ranges from 1% to 4%, and bridging fibrosis and severe inflammation have been described in approximately 15% [10, 25, 27–30]. Hepatocellular carcinoma (HCC) is rare, with only 3 cases described to date [31, 32]. Alongside co-infection with obligatory (HBV, HDV, HGV, TTV) and facultative (cytomegalovirus, Epstein-Barr virus, human herpesviruses types 1, 2, 6, etc.) hepatotropic viruses and high necroinflammatory activity in the liver, risk factors for cirrhosis in children with chronic HCV include: metabolic disorders (Wilson's disease, glycogen storage diseases types I–IV, rarely IX; cystic fibrosis, alpha-1 antitrypsin deficiency, galactosemia, tyrosinemia, and other aminoacidurias; congenital anomalies of the liver and biliary tract—primary sclerosing cholangitis, Alagille syndrome, etc.) [33].

Overall, chronic HCV infection is the dominant form of HCV infection in the pediatric population. When assessing the clinical presentation of chronic HCV in children, it is practical to distinguish the following disease courses and their corresponding clinical and epidemiological diagnostic criteria.

Chronic HCV Infection as Fetal Hepatitis:

Epidemiological diagnostic criteria: the child was born to an HCV-positive mother; increased risk factors include the mother having received no prior follow-up or treatment by an infectious disease specialist; high viral load around conception, throughout pregnancy, and prior to delivery; previously born children testing HCV-positive at birth and currently; maternal history of psychoactive substance use continuing after conception; maternal co-infection with HIV-1/2 or other genital tract/sexually transmitted infections, HBV, HDV, cytomegalovirus, Epstein-Barr virus, human herpesviruses types 1 and 2, etc.; invasive delivery; complicated obstetric and gynecological history, etc.

Clinical diagnostic criteria: in monoinfection, the majority of children develop primary chronic hepatitis, and virtually all present with an asymptomatic course without a distinct onset, showing mild hepatomegaly and, in some cases, splenomegaly (predominantly in infants and much less frequently in toddlers); signs of an ongoing active process, such as metabolic disturbances, are minimal (cytolytic syndrome at low to moderate, fluctuating levels) or absent (bilirubin, ALT, AST, ALP, and GGT levels within reference ranges); viremia levels range from low to high, indicating individual replication rates that rarely correlate with the biochemical activity of hepatic necroinflammation. Chronic HCV infection in this group of children remains asymptomatic for many years and, in the absence of active screening due to the maternal or sibling HCV status, is discovered incidentally—typically during workups for intercurrent illnesses (detection of cytolytic syndrome), preoperative evaluations, contact tracing around HAV or familial HBV outbreaks, or occasionally during routine admissions to preschools or schools. In some school-age patients, against the background of an enlarged, slightly tender, and firm liver, asthenic syndrome (increased fatigue and weakness after physical education classes or sports sections) and dyspeptic syndrome occur, manifesting as decreased appetite, food selectivity, and occasional right upper quadrant pain following physical exertion (biliary dyskinesia phenomena) [2, 11, 18-20, 24-25].

Chronic HCV Infection in Children and Adolescents as a Healthcare-Associated Infection (HAI):

Epidemiological diagnostic criteria: history of invasive procedures in inpatient or outpatient settings—frequent, multiple injections (post-injection); blood transfusions and short-lived blood components (packed red blood cells, leukocyte concentrate, fresh-frozen or dry plasma), pooled blood components (antihemophilic factors VIII, IX; platelet concentrate, etc.) (post-transfusion); indwelling catheters (vascular, urinary, nasal catheters, etc.) (catheter-associated); associated with other invasive procedures in the child—surgeries, endoscopic procedures, transplants including bone marrow, patients on hemodialysis or peritoneal dialysis (extremely high risk), etc.; high-risk groups include children of any age with hemato-oncological diseases, pediatric intensive care unit patients, children with chronic illnesses requiring frequent hospitalizations, and dental interventions in questionable or unlicensed dental offices.

Clinical diagnostic criteria: massive infection in a child presents with a distinct clinical and laboratory picture of mildly pronounced acute icteric hepatopathy (slight scleral and skin icterus), moderately enlarged, slightly tender, and firm liver resembling acute hepatitis C; adolescents may exhibit signs of fatigue, decreased appetite, intermittent abdominal pain, nausea, vomiting, a bitter taste in the mouth, spontaneous nosebleeds or other hemorrhages, bruising on the skin, abdominal distension, and prominent superficial veins on the anterior abdominal wall; high viremia levels (viral load >1,000,000 IU/mL). Mild telangiectasias and palmar erythema may occur in adolescents. Cytolytic syndrome is clearly pronounced in the early stages of the disease, fluctuates, and tends to normalize over a 7–10 year follow-up period [34, 35].

Chronic HCV Infection in Substance-Abusing Adolescents as Artificial Bloodborne Infection:

Epidemiological diagnostic criteria: adolescents using psychoactive substances (parenteral route carries maximum risk), vape users, individuals with marginal behavior, tattoos, body piercing, those from socially disadvantaged families, runaways, neglected children, and other risk factors; the HCV and drug use status of the parents must always be clarified.

Clinical diagnostic criteria: as a rule, a manifest icteric form occurs with moderate icterus of the mucous membranes, sclera, and skin; prominent metabolic disorders (hyperbilirubinemia due to the conjugated fraction, cytolysis syndrome) [36, 37].

Chronic HCV in adolescents as a sexually transmitted infection:

Epidemiological diagnostic criteria: sexually active adolescents, usually unprotected, of various types, especially with multiple partners, including sexual assault; special attention should be paid to those consuming energy drinks and other alcohol-containing beverages, as well as smokers, especially vape users (decreased self-control and increased risk-taking behavior); adolescents with deviant mental status; residents of institutionalized settings; runaways, neglected children, homeless individuals; girls represent a significantly higher risk group compared to boys; extremely rarely, the history may indicate accidental pregnancies. Concomitant gynecological diseases and sexually transmitted infections (markers of risky sexual behavior), inflammatory in nature and with ulcerations, may be present in the history and increase the risk of infection (syphilis, gonococcal infection, ureaplasmosis, genital herpes, genital chlamydia - urethritis, epididymitis, orchiepididymitis); frequent users of psychoactive substances, those with marginal behavior, from socially disadvantaged families, runaways, neglected children, and other adverse factors; the HCV status and drug status of the parents must always be clarified.

Clinical diagnostic criteria: symptoms of the infection are minimal or absent; the disease may remain unrecognized for a long time; in adolescent children with this mechanism of infection, the disease is often detected incidentally in connection with intercurrent illnesses (Gilbert's syndrome, etc.). In some adolescents, a manifest icteric form occurs with moderate icterus of the mucous membranes, sclera, and skin; prominent metabolic disorders (hyperbilirubinemia due to the conjugated fraction), cytolysis syndrome is significantly pronounced, undulating over time with a tendency to level off over a multi-year dynamic course of 7-10 years. A multi-year latent course is characteristic [38, 39].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The definitive diagnosis of hepatitis C is established based on the detection of HCV RNA in the patient's blood, regardless of the presence or absence of a characteristic symptom complex and/or abnormalities in laboratory test results, since in addition to clinically manifest forms, a latent course of the disease is also possible. The criterion for the differential diagnosis of acute and chronic hepatitis is the duration of the disease course. If the disease duration is less than 6 months, the diagnosis is formulated as acute hepatitis C.

Screening examination to rule out HCV infection is indicated for the following groups of children:

1. All children born to HCV-infected mothers

2. Brothers and sisters of children infected with HCV vertically (if they were born to the same mother)

3. Children of any age from a family focus of HCV

4. Children with immunodeficiency (patients with oncological diseases, patients on hemodialysis, patients receiving immunosuppressant therapy, etc.)

5. Children with liver disease of unclear etiology (during the primary clinical and laboratory examination)

6. Individuals belonging to risk groups for HCV transmission (adolescents: with a tendency to vagrancy; injection drug users; with early onset of sexual activity; with tattoos)

7. Individuals staying in closed institutions (orphanages, penitentiary institutions) - upon admission to the institution, and additionally - according to indications [40-42]

Screening examination for children from risk groups is best performed according to the following algorithm: blood test - determination of total classes M and G antibodies (anti-HCV IgG and anti-HCV IgM) to Hepatitis C virus in the blood (ELISA or CLIA). In case of a positive result, the determination of Hepatitis C virus RNA in the blood by PCR is additionally performed to confirm the diagnosis.

Examination of children with perinatal contact regarding viral hepatitis C is carried out at the age older than 2 months (preferably at the age of 4-6 months). Determination of antibodies in the blood is recommended, followed by the determination of Hepatitis C virus RNA in the blood by PCR (qualitative study) in the presence of antibodies. If negative PCR results and the absence of anti-HCV by blood ELISA are obtained at the age of 18 months, the child is deregistered as healthy. The detection of antibodies alone is not a sign of infection, since maternal antibodies can persist in the child's body during the first year and a half of life. At the same time, the prolonged persistence of antibodies is a reason for an in-depth examination to rule out the course of hepatitis C. If HCV RNA is detected in the child's blood at the age under 6 months, the diagnosis of «Acute viral hepatitis C» is established, and at the age older than 6 months - «Chronic viral hepatitis C». In case of infection and confirmation of the diagnosis (AVHC or CHVC), follow-up care (dispensary observation) is carried out similarly to older age groups.

Children with immunodeficiency must obligatorily undergo blood PCR with the determination of viral RNA, regardless of the presence or absence of antibodies to the hepatitis C virus, since antibodies may be absent in them due to an immune defect.

2.1 Complaints and Anamnesis

2.2 Physical Examination

At the stages of diagnosis, examination before the start of antiviral therapy (AVT), during its implementation, and follow-up care:

Comments: Palpation determines the size of the liver and spleen, the consistency of the organs, the characteristics of the edge, and the presence or absence of tenderness. Percussion determines the size of the liver and the presence of effusion in the abdominal cavity [2, 20]. The younger the child, the more frequently splenomegaly is recorded. The severity of hepatomegaly and splenomegaly correlates with the severity of the disease. The cardiovascular, nervous, urinary, and other systems are often involved in the process, but these changes are never leading.

2.3 Laboratory Diagnostics

At the diagnostic stage:

Comments: This examination allows evaluating the presence and activity of cytolysis and cholestasis syndromes, as well as the protein-synthesizing function of the liver. The de Ritis ratio (AST:ALT ratio) >1.0 indicates the possibility of a prolonged inflammatory process in the liver.

Comments: An important feature of the course of HCV infection in children during the first 3 years of life is a fairly high percentage of spontaneous viral clearance (35-45%). However, this largely applies to transfusion-acquired HCV. Whereas in perinatal hepatitis, the frequency of spontaneous viral clearance, according to various authors, ranges from 2.4% to 18%, and isolated studies indicate higher figures—up to 50% [11, 18-20, 44].

At the dispensary follow-up stage:

In patients prior to antiviral therapy

Comments: Performed for dynamic monitoring of indirect signs of chronic viral infection (lymphocytosis, ESR), anemia, leukopenia, and thrombocytopenia.

Comments: direct-acting antiviral agents are prescribed only in the presence of hepatitis C virus RNA; the presence of antibodies to hepatitis C virus is not an indication for prescribing these drugs

In patients who have completed a course of antiviral therapy

Comments: When treating with direct-acting antivirals (DAAs), HCV RNA must be tested 12 weeks after the end of therapy.

If the test result is negative, the patient is considered a convalescent and is discharged from dispensary follow-up.

Comments: Performed for dynamic monitoring of the efficacy of the therapy (reduction in the severity of cytolysis and intrahepatic cholestasis syndromes, improvement of hepatic synthetic function). Assessment of biochemical markers of liver damage is important because it allows for suspected disease relapse in cases of low viral load (below the threshold of sensitivity of test systems).

2.4 Instrumental Diagnostics

In patients prior to antiviral therapy

Comments: Abdominal ultrasound is used to assess the size and structure of the liver, spleen, pancreas, lymph nodes, vascular condition, and the presence or absence of ascites to diagnose space-occupying lesions and rule out concomitant gastrointestinal pathology. In some cases, this may be decisive in determining the stage of the disease and choosing treatment tactics. Patients with unclear focal lesions in the liver and spleen or uncertain, contradictory ultrasound findings require advanced instrumental examination [50-51].

Comments: Endoscopic examination is performed to diagnose the grade of esophageal varices, as well as to place clips and bands during bleeding or for the prevention of esophageal variceal bleeding in patients with liver cirrhosis.

Comments: Contrast-enhanced CT and MRI have high diagnostic accuracy in detecting small neoplasms; this examination is necessary for the early detection of hepatocellular carcinoma

In patients who have completed a course of antiviral therapy

2.5 Other Procedures

No.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment tactics are chosen based on the following factors [11, 74-79, 114]:

• age of the sick child;

• molecular and genetic characteristics of chronic hepatitis C;

• presence and nature of complications;

• severity of liver fibrosis;

• prior history of chronic hepatitis C therapy

The child's regimen and diet are determined by the attending physician depending on the child's age, trophic and somatic status, and presence of comorbid conditions

3.1 Conservative Treatment

3.1.1 Etiotropic (antiviral) therapy.

Antiviral therapy regimens

Currently, interferon-free treatment regimens using direct-acting antivirals (DAAs) are available. The World Health Organization (WHO) recommends abandoning interferon-based regimens for the treatment of chronic hepatitis C virus (HCV) infection in children, which is also supported by major international professional associations—the European and American Associations for the Study of the Liver—as well as Russian professional societies, including the National Scientific Society of Infectious Diseases, the Russian Society for the Study of the Liver, and the Russian Gastroenterological Association [42,65–68]. The use of pangenotypic treatment regimens is advisable. As of October 2024, two pangenotypic drugs for the treatment of chronic HCV in children are registered in the Russian Federation: glecaprevir+pibrentasvir** and velpatasvir+sofosbuvir** (for children aged 12 years and older). The genotype-specific drug ledipasvir+sofosbuvir may also be used. The choice of drug is made by the attending physician based on the patient's age and comorbid conditions (in accordance with drug contraindications and potential drug-drug interactions) [42, 47, 65-83, 111,114].

Comments: The drug is prescribed for patients with a body weight from 12 kg to 45 kg who are treatment-naive or have previously been treated with interferon alfa-2b in rectal suppositories, without liver cirrhosis or with compensated liver cirrhosis. The daily dose of the drug depends on body weight. The duration of therapy is 8 weeks [111].

Comments: according to the instructions for medical use, its administration is approved for children aged 12 years and older, as well as for children under 12 years of age with a body weight of more than 45 kg. For patients who are treatment-naive or have previously received treatment with interferon alfa-2b in rectal suppositories, the duration of treatment is 8 weeks [48, 49, 71, 74-78, 83].

Comments: according to the instructions for medical use, its administration is approved for children over 12 years of age or with a body weight of more than 30 kg [72, 74-82, 119].

Comments: Recommended regimen and duration of treatment: for patients infected with genotype 1, 4, 5, or 6, the drug is prescribed for a 12-week course. For treatment-naive patients with genotype 1 and without liver cirrhosis, the treatment duration can be shortened to 8 weeks [73,­79,81].

3.1.2 Pathogenetic therapy

• In children over 12 years of age with chronic viral hepatitis C, it is recommended to prescribe drugs for the treatment of liver diseases, glycyrrhizic acid + phospholipids, prior to antiviral therapy as pathogenetic therapy in the absence of clinical and laboratory signs of cholestasis [84-87, 120].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Comments: The use of other hepatoprotective drugs (ATX group A05BA (Drugs used in liver diseases)) is acceptable [84-87].

Comments: For children under 3 years of age, in the form of a suspension; for children over 3 years of age, capsules.

Comments: Infusions of 10-20% human albumin solution** or fresh frozen plasma are performed if serum albumin levels drop below 30 g/L, or in the formation of non-protein edema and ascites [93].

3.1.3 Symptomatic therapy

Used depending on the symptomatology of comorbid diseases/conditions

3.2 Surgical Treatment

Comments Endoscopic variceal ligation is performed both for the prevention of bleeding and for its management.

Level of reliability of recommendation C (level of conviction of evidence — 4)

Comments: Additional diagnostic workup is performed in accordance with the management protocol for patients on the waiting list at a transplant center [105-108, 128, 129].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

- Specialized rehabilitation measures have not been developed for patients with CHC.

- CHC is not a contraindication for sanatorium-resort treatment.

5. Prevention and Dispensary Observation

5.1 Prevention

Specific prevention of viral hepatitis C has not been developed at present.

5.2 Dispensary monitoring

Follow-up monitoring prior to the course of antiviral therapy

Comments: In case of disease exacerbation, the administration of pathogenetic drugs is acceptable outside of scheduled courses as well [2, 7].

Follow-up monitoring after the course of antiviral therapy

Comments: after a course of AVT, the examination is performed 12 weeks after the end of the course.

Individuals with spontaneous virus elimination who have no detectable HCV RNA during dynamic follow-up for 2 years at the recommended frequency of at least once every 6 months are considered convalescents and are eligible for discharge from dispensary registration.

6. Organization of Medical Care

Medical care is provided in the following forms:

• emergency medical care;

• urgent medical care;

• planned medical care.

Conditions for the provision of medical services

Medical care is provided in the form of:

• primary health care;

• emergency medical care, including specialized emergency medical care;

• specialized, including high-tech, medical care. Medical care for children with chronic hepatitis C (CHC) can be provided under the following conditions:

• outpatient (in settings not providing round-the-clock medical observation and treatment);

• in a day hospital (under conditions providing medical observation and treatment during the day, not requiring round-the-clock medical observation and treatment);

• inpatient (in settings providing round-the-clock medical observation and treatment).

• in the anesthesiology and intensive care unit (ICU) with hourly monitoring.

Primary health care is provided to patients on an outpatient basis and in a day hospital setting.

Primary paramedic-led health-care in outpatient settings is provided at feldsher-midwifery stations.

Primary health care is provided by a district pediatrician, general practitioner (family doctor) in an outpatient setting.

Primary specialized health care is provided by an infectious disease specialist, pediatrician, general practitioner, or gastroenterologist of a medical organization providing medical care to outpatients.

Specialized, including high-tech, medical care is provided in an inpatient setting by infectious disease specialists and other specialist physicians and includes the prevention, diagnosis, treatment of diseases and conditions requiring the use of special methods and complex medical technologies, as well as medical rehabilitation.

Treatment of patients is carried out in an inpatient setting (in pediatric, gastroenterological, or infectious disease departments) upon referral by a district pediatrician, general practitioner (family doctor), infectious disease specialist, or medical workers who detected CHC.

If there are signs of decompensated liver function, the patient is hospitalized in inpatient facilities equipped with an intensive care unit.

The decision on patient discharge from the hospital is individual and made by the attending physician depending on the clinical situation (patient's condition).

7. Additional Information

7.1 HCV and HBV Coinfection [109-111].

Treatment of patients with chronic mixed hepatitis B+C is carried out in accordance with current guidelines for the treatment of chronic HBV or chronic HCV monoinfection, depending on the presence and severity of replication of the first or second virus.

In most cases, in patients with chronic mixed hepatitis B+C, HBV replication is suppressed or remains within values corresponding to the immune control phase of chronic HBV infection.

The risk of HBV reactivation during CHC AVT is possible and difficult to predict. In this regard, careful monitoring of the replicative activity (viral load) of HBV and serum aminotransferase activity is required [2].

7.2 HCV and HIV coinfection

Treatment of children with CHC and HIV infection is carried out according to the CHC treatment regimen.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

The clinical guidelines "Chronic Viral Hepatitis C in Children" were developed by members of the Association of Infectious Disease Physicians of Saint Petersburg and the Leningrad Region (RO "AVISPO") and the Euro-Asian Society for Infectious Diseases (RO "EAOIB").

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Physicians of all specialties (including epidemiologists)

2. Medical students;

3. Clinical residents, postgraduate students.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Scale for assessing grades of recommendation (GR) for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 157-FZ of September 17, 1998 (as amended on June 11, 2021) "On Immunoprophylaxis of Infectious Diseases"

2. Federal Law No. 326-FZ of November 29, 2010 (as amended on February 24, 2021) "On Compulsory Medical Insurance in the Russian Federation."

3. Federal Law No. 323-FZ of November 21, 2011 (as amended on July 2, 2021) "The Fundamentals of Healthcare Protection in the Russian Federation."

4. Order of the Russian Ministry of Health No. 804n of October 13, 2017 "On Approval of the Nomenclature of Medical Services" (as amended on September 24, 2020)

5. Order of the Russian Ministry of Health of December 6, 2021 No. 1122n

6. "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations by Epidemiological Indications, and the Procedure for Conducting Preventive Vaccinations" (Registered on December 20, 2021 No. 664356).\Order of the Russian Ministry of Health of May 2, 2023 No. 205n (as amended on December 4, 2023) "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers" (Registered with the Ministry of Justice of Russia on June 1, 2023 No. 73664)

7. Order of the Russian Ministry of Health of October 7, 2015 No. 700n (as amended on December 9, 2019) "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education" (Registered with the Ministry of Justice of Russia on November 12, 2015 No. 39696)

8. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care" (Registered with the Russian Ministry of Justice on May 17, 2017, No. 46740)

9. Information Letter of the Russian Ministry of Health of April 14, 2014 (updated November 30, 2017) "On Improving the Provision of Medical Care to Patients with Chronic Viral Hepatitis";

10. Sanitary Rules and Norms SanPiN 3.3686-21 "Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases" (approved by the Decree of the Chief State Sanitary Doctor of the Russian Federation of January 28, 2021 No. 4);

11. Order of the Ministry of Health and Social Development of the Russian Federation of May 5, 2012 No. 521n "On Approval of the Procedure for Providing Medical Care to Children with Infectious Diseases" Registered with the Ministry of Justice of the Russian Federation on July 10, 2012. Registration No. 24867;

12. Order of the Ministry of Health of the Russian Federation of September 23, 2020 No. 1008n "On Approval of the Procedure for Providing Patients with Therapeutic Nutrition" (Registered with the Ministry of Justice of the Russian Federation on September 30, 2020 No. 60137)

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Chronic viral hepatitis C is an infectious disease caused by the hepatitis C virus. The primary target organ affected in this infection is the liver. The disease affects both adults and children regardless of sex. Currently, approximately 58 million people worldwide are infected. In Russia, about 55,000 new infection cases are registered annually.

The main route of infection in children is the transmission of the virus from an infected mother to her child during pregnancy and childbirth. Transmission from mother to child during pregnancy and childbirth does not always occur; about 5–10% of newborns become infected. Concomitant HIV infection, obstetric interventions, and a prolonged anhydrous period significantly increase the risk of infection. Currently, there are no methods of drug prevention for mother-to-child transmission of the virus. In addition, a child can be infected with the hepatitis C virus during procedures involving breaks in the skin integrity if infected instruments are used—surgical interventions, reuse of syringes, as well as hemodialysis, dental procedures, sharing razor blades, acupuncture, tattoos and piercings, manicures and pedicures. In adolescents, infection is also observed with intravenous drug use, and the virus can be sexually transmitted. Work on developing a vaccine against hepatitis C is underway worldwide, but so far it has not been successful.

The news that you or your child is infected with HCV can be overwhelming. There are schools for patients with chronic hepatitis C where experienced infectious disease specialists and psychologists will certainly help you. Consult an infectious disease specialist with experience in treating chronic hepatitis C.

You are not obligated to inform others that you are infected, but you should strive to prevent infecting other people. Make sure you have your own individual toothbrush, shaving accessories, and manicure and pedicure tools. Alcohol consumption must be avoided. Sports activities can be continued. In general, a normal healthy lifestyle is recommended.

Hepatitis C is currently fully curable. It is treated with medications, including antiviral drugs in pill form. There are treatment regimens using subcutaneous injections. Modern antiviral therapy for chronic hepatitis C allows the disease to be cured without affecting a person's lifestyle or personality. It does not cause numerous adverse events and psychological changes associated with the need to undergo treatment. Anxiety, tension, fear, agitation, depression, and hope are normal reactions for many patients.

To prevent infection in a future child, it is strongly recommended to undergo treatment for chronic hepatitis C at the pregnancy planning stage, before conception. The medications used to treat hepatitis will not affect reproductive health or the health of the unborn child. However, the use of these agents is not recommended during pregnancy, so contraception must be used during therapy.

To prescribe therapy for you or your child, you must consult an infectious disease specialist and undergo an examination to rule out contraindications.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Criteria for assessing the severity of liver fibrosis (cirrhosis).

Liver fibrosis stage assessment scale METAVIR (Meta-analysis of histological data in

viral hepatitis) – Meta-analysis of histological data in

Source: Bedossa, P., Poynard, T., and The METAVIR cooperative study group. An algorithm for the

grading of activity in chronic hepatitis C. Hepatology. 1996; 24: 289 – 293

Type: rating scale

Purpose: assessment of the degree of liver fibrosis

Content and key:

Liver elasticity values at various stages of fibrosis (transient fibroelastometry) (Liver elastometry)

F0 - less than 6.2 kPa - no fibrosis

F1 - 6.2-8.3 kPa - minimal fibrotic changes in the liver. Star-like widening of portal tracts without septum formation

F2 - 8.3-10.8 kPa - moderate fibrotic changes in the liver. Widening of portal tracts with isolated portoportal septa

F3 - 10.8-14 kPa - severe fibrotic changes in the liver. Numerous portocentral septa without cirrhosis

F4 - more than 14 kPa - liver cirrhosis

Child-Pugh score - Child-Pugh

Source: Durand F., Valla D. Assessment of the prognosis of cirrhosis: Child–Pugh versus MELD

//Journal of hepatology. – 2005. – Vol. 42. – No. 1. – P. S100-S107

Type: rating scale

Purpose: assessment of the degree of hepatic failure

Contents:

*Assessment of the degree of hepatic encephalopathy:

• None (1 point)

• Grade I: Mood swings / confusion

• Grade II: Inappropriate behavior, developing stupor, lethargy

• Grade III: Marked confusion, stupor, but arousable

• Grade IV: Comatose / unresponsive

Key (interpretation): The severity of liver cirrhosis is assessed by a point system calculated based on 5 or 6 parameters. There are three established classes: A, B, and C:

5–6 points: Child-Pugh Class A

7–9 points: Child-Pugh Class B

10–15 points: Child-Pugh Class C

Histological Activity Index (Knodell index)

Source: Knodell R.G., Ishak K.G. Black W.C. [et al.] Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis / R.G.

Knodell, K.G. Ishak, W.C. Black [et al.] // Hepatology. – 1981. – Vol. 1(5). – P. 431–435

Type: scoring index

Purpose: assessment of the severity of morphological disorders in the liver

Contents:

Key (interpretation): 0 = no activity

1-4 = minimal activity

5-8 = low activity

9-12 = moderate activity

13-18 = high activity