Chronic Hepatitis B (CHB) in Children: Clinical Guidelines

List of Abbreviations

ANA – antinuclear antibodies

ASMA – anti-smooth muscle antibodies

ALKM-1 – anti-liver-kidney microsomal type 1 antibodies

HBcAg – Hepatitis B virus core antigen

HBeAg – Hepatitis B virus e antigen

HBsAg – Hepatitis B virus surface antigen

HBV – Hepatitis B virus

HBxAg – Hepatitis B virus x antigen

HDV – Hepatitis D virus

IgM, IgG – Immunoglobulins class M, G

METAVIR – scale for assessing the severity and activity grade of hepatic fibrosis

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

YMDD – mutation in the HBV genomic region during NRTI therapy

BP – Blood pressure

ALT – Alanine aminotransferase

Anti-HBe – Antibodies to HBe antigen

Anti-HBs – Antibodies to hepatitis B surface antigen

Anti-HDV – Antibodies to hepatitis D virus

Anti-HBc – Antibodies to hepatitis B core antigen

AST – Aspartate aminotransferase

AFP – alpha-fetoprotein

WHO – World Health Organization

HB – Hepatitis B

GGT – Gamma-glutamyl transpeptidase

DIC – Disseminated intravascular coagulation

Biliary dyskinesia

DNA – Deoxyribonucleic acid

Biliary tract

Mechanical ventilation

Infectious toxic shock

ELISA – Enzyme-linked immunosorbent assay

IFN-α 2b – Interferon alfa-2b**

cccDNA – Covalently closed circular DNA

MO – Medical organization

Ministry of Health of the Russian Federation – Ministry of Health of the Russian Federation

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

INR – international normalized ratio

NRTI – Nucleoside and nucleotide reverse transcriptase inhibitors

CBC – Complete blood count

Urine analysis – General clinical urinalysis

ICU – Department of anesthesiology, resuscitation, and intensive care

AHB – Acute hepatitis B

ALF – Acute liver failure

AVT – antiviral therapy

PT – prothrombin index

PCR – Polymerase chain reaction

rcDNA – Relaxed circular double-stranded DNA

NWFD – Northwestern Federal District

ACD – Average course dose

ESR – Erythrocyte sedimentation rate

ASD – Average daily dose

FL – Federal Law

CHB – Chronic hepatitis B

CLIA – Chemiluminescent immunoassay

RR – Respiratory rate

HR – Heart rate

ALP – Alkaline phosphatase

Terms and Definitions

Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence (clinical research results) in making decisions about the care and treatment of individual patients.

Disease – a disturbance of bodily function, working capacity, and the ability to adapt to changing environmental conditions arising from the impact of pathogenic factors, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Instrumental diagnostics – diagnostics using various devices, apparatuses, and instruments to examine a patient.

Disease outcomes – the medical and biological consequences of a disease.

Quality of medical care – a set of characteristics reflecting the timeliness of medical care, the correctness of the choice of prevention, diagnosis, treatment, and rehabilitation methods in providing medical care, and the degree of achievement of the planned result.

Clinical guidelines are documents based on proven clinical experience that describe a physician's actions regarding the diagnosis, treatment, rehabilitation, and prevention of diseases, helping them make correct clinical decisions.

Clinical situation refers to a case requiring the regulation of medical care regardless of the specific disease or syndrome.

Laboratory diagnostics is a set of methods aimed at analyzing test material using various specialized equipment.

Medical intervention encompasses types of medical examinations and/or medical manipulations performed by a medical professional in relation to a patient, affecting their physical or mental state and having a preventive, exploratory, diagnostic, therapeutic, or rehabilitative purpose, as well as artificial termination of pregnancy.

Level of certainty of evidence – reflects the degree of confidence that the found effect of a medical intervention is true.

Level of recommendation certainty – reflects not only the degree of confidence in the validity of the intervention's effect, but also the degree of confidence that following the recommendations will bring more benefit than harm in a specific situation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic hepatitis B (CHB) is an infectious and inflammatory liver disease lasting more than 6 months, based on necrosis with lymphomonocytic infiltration of the hepatic lobules and portal tracts, caused by the DNA-containing hepatitis B virus (Hepatitis B virus - HBV), with parenteral and blood-contact mechanisms of infection and natural and artificial transmission pathways [1,2,3,4]. The disease is characterized by clinical polymorphism, variable course, and outcomes: from latent forms without clinical manifestations to highly active (aggressive) ones. In late stages, it is associated with the development of liver cirrhosis and/or hepatocellular carcinoma, and it may remain unchanged or regress under the influence of therapy or spontaneously. In its chronic course, hepatitis B manifests as a systemic infection [1,2,3,4,5,7].

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

Etiology. The causative agent of CHB—the hepatitis B virus—is a small DNA-containing virus belonging to the family Hepadnaviridae, genus Orthohepadnaviridae. HBV is characterized by high tissue and species specificity, unique genome organization, and replication mechanisms [6,8,9,10,11,12,13].

The HBV virion (the virus outside the host cell) is a particle 42–45 nm in diameter, consisting of a lipoprotein envelope (supercapsid), an inner shell (capsid), and a nucleoprotein (DNA) [1,8,10,12,13]. The supercapsid is a lipid membrane into which outer envelope antigen proteins are embedded—specifically HBsAg ("Hepatitis B surface Antigen"). In historical sources, HBsAg may be referred to as the "Australian antigen." The antigen was named "Australian" by its discoverer, B.S. Blumberg, because it was first detected in the blood of Australian Aborigines. In addition to HBsAg, the supercapsid contains pre-S1 and pre-S2 proteins [1,8,9,10,12,13]. The capsid (nucleocapsid) has an icosahedral (polyhedral) shape with a size of 28 nm. The capsid contains HBcoreAg/HBcAg (Hepatitis B core Antigen), its subunit HBeAg (transformed HBcAg), and HBxAg. Inside the capsid are enzymes—DNA polymerase, reverse transcriptase—and a nucleoprotein representing the genetic material of the virus. The HBV genome has an atypical structure and is represented as relaxed circular partially double-stranded DNA [1,8,10,12,13].

HBV DNA has 4 open reading frames encoding 7 proteins:

• gene P (polymerase): Pol/RT HBV — polymerase, reverse transcriptase;

• gene S (surface): pre-S1, pre-S2, HBsAg;

• gene C (core): HBcAg, HBeAg;

• gene X: HBxAg [10, 12, 13].

Viral antigens and their corresponding antibodies reflect the stage of the infectious process (for details, see the "Diagnostics" section). Each HBV protein has its own function and plays a role in the viral life cycle. HBsAg, together with pre-S1 and pre-S2 proteins, is responsible for viral integration into hepatocytes. HBcAg has high immunogenicity, which is associated with an adequate immune response of the body. HBcAg can only be detected inside hepatocytes. A transformed variant of HBcAg circulates in the peripheral blood—HBeAg—which is a marker of active viral replication and high DNA polymerase activity. HBxAg activates the expression of all viral genes and enhances the synthesis of viral proteins [1,8,9,10,12,13].

Recent studies demonstrate a special role of HBxAg in the development of epigenetic mutations and oncogenesis (the formation of hepatocellular carcinoma) [11,14,15,16]. Mutations occurring in specific gene regions, especially those responsible for the pre-S—pre-S1 and pre-C zones, lead to the formation of new mutant viral strains [10,17].

The most conserved antigenic determinant is the a-determinant (HBsAg), mutations in which lead to vaccine escape [18,19,20,21,22].

To date, 10 HBV genotypes (A–J) have been described, with a nucleotide sequence divergence of about 8% among them. The best-studied variants are A–D [10,17,23].

The genotypes exhibit a phylogenetically established geographical distribution (Table 1). Differences between them are of clinical significance, as they affect treatment efficacy, the frequency of chronic infection development, disease severity, etc. [11,12,13,24]. Currently, the clinical role of HBV genotypes is not yet fully understood, and research in this direction is ongoing worldwide. In our country, genotype D is the most common [25].

Table 1. Geographical distribution of various HBV genotypes [17,25].

The virus is extremely stable in the external environment and remains viable at room temperature for 3 months, upon freezing for 15–20 years, in a domestic refrigerator for up to 1 year, and when heated to 60°C for 4 hours. It is resistant to lyophilization, ultraviolet radiation, ether, and low concentrations of chlorine-containing substances and formalin. Inactivation of the virus via autoclaving occurs in 45 minutes, and via dry-heat sterilization in 60 minutes. A 1–2% chloramine solution inactivates the virus in 2 hours, and a 1.5% formalin solution in 7 days [1,2,3,5,6,2].

Pathogenesis. After entering the human body (infection), HBV enters the liver via the bloodstream. HBsAg has a high affinity for receptors located on the surface of hepatocytes; their interaction ensures the virus enters the cell [1,26]. Subsequently, the virus sheds its envelope and enters the hepatocyte nucleus in the form of relaxed circular double-stranded DNA (rcDNA). In the nucleoplasm, rcDNA is transformed into covalently closed circular DNA (cccDNA), wrapped around histone and non-histone proteins to form a "beads-on-a-string" structure [1,10,11,12,27]. CccDNA serves as the transcription template for HBV and is the direct cause of chronic infection and viral persistence. Inside the hepatocyte nucleus, it exists as a mini-chromosome. The maintenance of cccDNA is necessary for viral persistence. Subsequently, using polymerase, new rcDNA is synthesized on the pregenomic RNA template [9,11,12,87,28,29,30].

HBV is not inherently cytotoxic. An excess of synthesized HBsAg and HBeAg enters the bloodstream, and virus assembly culminates in the presentation of HBcAg and HBeAg on the hepatocyte membrane, resulting in their "recognition" by immunocytes. The interaction between the virus and the host's immune system activates various components of this system (T- and B-lymphocytes, macrophages, and cytokines, with the T-cell response playing the leading role) [18,21,27,31,32]. Hepatocyte cytolysis, virus elimination, and the outcome of hepatitis B depend on the body's immune response: the production of endogenous interferon, the activity of natural killer cells, cytotoxic T lymphocytes, antibody-dependent killers, macrophages, and antibodies against HBV antigens, liver-specific lipoprotein, and a number of altered liver tissue structures. This results in the development of necrobiotic and inflammatory changes in the liver parenchyma. As a result of pathological changes in liver tissue, cytolytic, mesenchymal-inflammatory, and cholestatic syndromes develop, accompanied by specific clinical and laboratory manifestations. T cells exert both a direct cytolytic effect and an indirect antiviral effect through the expression of antiviral cytokines (interferons) and the activation of B cells that produce neutralizing antibodies, which prevent viral spread. Cell damage occurs via an immune-mediated mechanism. The course and outcome of the disease depend on many factors, including the nature and severity of the immune response, age, genetic determination, and characteristics of the virus itself. An adequate immune response leads to a severe clinical course, but ultimately results in viral elimination. A hyperimmune response may trigger autoimmune processes. Conversely, a weak immune response causes low disease activity, resulting in a mild or even subclinical course of hepatitis. However, such subclinical and mild forms carry a significantly higher probability of developing into chronic hepatitis [8,9,18,21,32].

Integration of the HBV genome into the hepatocyte genome is one of the mechanisms underlying the development of persistent (acyclic) forms of hepatitis B and primary hepatocellular carcinoma. The humoral response consists of the accumulation of specific antibodies (anti-HBc, anti-HBe, anti-HBs) and their binding to the corresponding antigens, thereby terminating the free circulation of antigens in the blood [9,11,12].

Chronic hepatitis B develops in 80–90% of infants infected during the perinatal period, in 30–60% of children infected under the age of 6 years, and in less than 5% of otherwise healthy adults [33,34,35,36].

The immune response is genetically determined and associated with human leukocyte antigens (HLA). Patients with a hyperimmune response most frequently show B8 and A1-B8 antigens in their blood, whereas those with a delayed or weakened response show B7, B18, and B35 [37]. Recent studies point to a novel antiviral gene INTS10 (chromosomal localization 8p21.3) that suppresses HBV replication in liver cells via the type 3 interferon-dependent regulatory factor and promotes viral elimination from the body [37,38].

Extrahepatic viral replication has been proven to occur in blood cells, bone marrow, spleen, and lymph nodes. This allows HBV to "escape" immune surveillance, as lymphocytes and monocytes are not monitored by immunocytes. Other pathways of viral persistence and chronic progression include the ability of the virus to integrate its genetic material into the hepatocyte genome and its capacity for mutation. Mutations in various regions of the HBV genome have been described, leading to the generation of therapy-resistant viruses (precore mutant, YMDD mutant) or variants that are not neutralized by antibodies produced in response to currently available commercial vaccines [1,9,21,27,31].

Viral elusiveness is one of the reasons for the chronic course of the infection. Mutant "vaccine-escape" strains of the virus are a major cause of hepatitis B incidence among vaccinated children [6,9,23,26,30].

1.3 Epidemiology of the Disease or Condition

Hepatitis B is an anthroponotic infection. The source of infection is always a human—an individual sick with various forms of hepatitis B (acute—the patient is contagious from the middle of the incubation period until the complete clearance of the virus from the body—and chronic). Patients with asymptomatic forms of hepatitis B pose a particular hazard, and all variants of manifest chronic infection can present a lifelong danger as a source of transmission [9,16,39,40]. The mechanism of transmission is parenteral (blood-borne). Infection can occur via both natural and artificial routes. Natural routes include sexual, domestic (blood-borne), and perinatal transmission. Transmission occurs through contact with blood, blood products, semen, saliva, and vaginal secretions from individuals with overt or subclinical forms of acute and chronic hepatitis B, as well as HBsAg carriers, during minor household injuries (manicures, hairdressing with sharp combs, sharing a razor, etc.) and through sexual contact [1,3,5,6,7,9,41,42].

Among children, the perinatal route—infection of the fetus and newborn during pregnancy and childbirth—is the most frequently realized [1,9,12,33,35,43]. Studies have shown that newborns of HBsAg- and HBeAg-positive mothers have a higher risk of infection (70–100% according to studies in Asia and 40% according to African studies) compared to those whose mothers are positive only for HBsAg (5–30% in Asia and 5% in Africa) [39]. The highest risk of infection occurs in children born to mothers with a high viral replication rate and biochemical activity [44]. Several authors indicate that cesarean section reduces the risk of perinatal HBV transmission from HBsAg-positive mothers [9]. Breast milk is not a risk factor for transmission [31].

In older children and adults, the primary routes of infection are medical and non-medical procedures accompanied by damage to the skin and mucous membranes. HBV transmission via transfusion of infected blood and blood components or during instrumental examinations in healthcare settings is possible, but is recorded extremely rarely today. The leading routes of transmission are non-medical—infection through broken skin and mucous membranes during intravenous drug use, tattooing, piercing, ritual practices, and cosmetic, manicure, pedicure, and other procedures using contaminated instruments [1,12,31,39,41].

The infectivity of HBV is 500–1000 times higher than that of HIV; as little as 0.0005 ml of blood is sufficient for transmission [8]. The virus is capable of surviving outside the human body while retaining virulence for at least 7 days. The incubation period averages 75 days, ranging from 30 to 180 days [3,8,9,12]. Patients with acute hepatitis B are epidemiologically dangerous from the end of the incubation period until full recovery, whereas in chronic infection, this timeframe is unlimited. According to WHO estimates, only about 10% of infected people worldwide are aware of their chronic hepatitis B status. This fact is of great concern because individuals living with hepatitis B, unaware of their contagiousness, pose a major threat as a "hidden" reservoir of infection [41,45].

In June 2021, the WHO published the "Interim guidance for country validation of viral hepatitis elimination", according to which the number of people living with hepatitis B globally in 2019 was approximately 296 million; in other words, 3.8% of the global population is infected with HBV [45].

Disease incidence varies significantly across different regions. For instance, in the African Region (82 million people) and the Western Pacific Region (116 million people), approximately 6.7% of the population lives with HBV infection. In Southeast Asia, about 60 million people are infected. At the same time, rates are significantly lower in the European and Region of the Americas—15 million and 5 million, respectively [43]. The majority of patients in high-endemicity HBV countries were infected via the perinatal route, prior to the introduction of hepatitis B vaccination programs [45]. Thus, a substantial decrease in the prevalence of HBV infection can be expected in the future. Significant success has already been achieved: according to recent WHO estimates, the proportion of children under five years of age chronically infected with HBV has dropped to 0.9% (2019), compared to 4.7% before the vaccination era (1980s–early 2000s) [41,45]. Nevertheless, despite the availability of a highly effective vaccine, approximately 1.5 million people are newly infected worldwide each year [45].

1.4 Features of Coding the Disease or Condition

B18.1 – Chronic viral hepatitis B without delta-agent

1.5 Classification of the disease or condition

1.5.1 By stages of the pathological process in the natural history of HBV infection

(5 phases are distinguished):

• HBeAg-positive chronic HBV infection

• HBeAg-positive chronic hepatitis B

• HBeAg-negative chronic HBV infection

• HBeAg-negative chronic hepatitis B

• HBsAg-negative HBV infection (occult hepatitis B)

This classification was adopted in 2017 by the European Association for the Study of the Liver (EASL), since previously used phase names are not supported by immunological data and are not determinants in deciding on indications for antiviral therapy. The proposed new formulation of the diagnosis is based on describing two main characteristics of chronicity: infection/hepatitis [3,5,6,7,9,12,46].

Table 2 — Classification of the phases of the pathological process in patients with chronic HBV infection

In the case of a chronic course resembling hepatitis, the disease is assessed by the level of virological and biochemical activity, the presence of complications, and the degree of fibrosis [2,3,5,6,7,9,12,47]:

1.5.2. By phases of replicative activity of the infectious process:

• replicative

• integrative

1.5.3 By cytolytic syndrome activity:

• without cytolytic activity

• low cytolytic activity

• moderate cytolytic activity

• high cytolytic activity

1.5.4. By fibrosis stages:

• F0 – no fibrosis

• F1 – mild fibrosis

• F2 – moderate fibrosis

• F3 – severe fibrosis

• F4 – liver cirrhosis

Appendix G1 presents the METAVIR liver fibrosis staging table , Appendix G2 shows the Child-Pugh cirrhosis score, and Appendices G3, G4 provide calculations for the APRI and FIB-4 fibrosis indices.

1.5.5 By presence of complications:

• without complications

• with complications

It is standard practice to assess replicative and viral activity by the viral load (VL) level, which is categorized as: "low" (up to 200 IU/mL) and "high" (more than 20,000 IU/mL). It is permissible to designate a "moderate" VL, which refers to an HBV DNA quantity from 2,000 IU/mL to 20,000 IU/mL [2,6,7,9,12].

The activity of the cytolytic syndrome is assessed by the fold elevation of ALT and AST levels above the upper limit of normal (ULN): minimal — 1.5–2 times the upper limit of normal; low — 2–5 times; moderate — 5–10 times; pronounced (high) — more than 10 times the ULN [3,5,6,7].

Examples of diagnosis formulation:

Preliminary diagnosis (newly diagnosed disease — suspected CHB / probable CHB case): Chronic hepatitis B (blood ELISA — HBsAg positive, anti-HBc positive);

Clinical diagnosis (confirmed CHB case): HBeAg-positive chronic hepatitis B (HBsAg positive, HBeAg positive, HBV DNA positive), high viral load, moderate activity grade, fibrosis stage F₁ by METAVIR.

Final (definitive clinical) diagnosis of CHB: B18.1 HBeAg-positive chronic hepatitis B (HBsAg positive, HBeAg positive, HBV DNA positive), high VL, high activity grade. Complication: Liver cirrhosis, Child-Pugh class B . Portal hypertension: esophageal varices grade II.

1.6 Clinical presentation of the disease or condition

The clinical presentation of CHB is highly variable, ranging from an asymptomatic carrier state to severe cholestatic forms with the development of liver cirrhosis and fibrosis, and depends on the phase of the pathological process, as mentioned above. However, in the majority of children with perinatal infection, HBV infection is paucisymptomatic. Hepatomegaly may be the only clinical manifestation of the disease. Jaundice of the skin and mucous membranes is usually mild and short-lived (bilirubin elevation up to 2–6 times normal). Hyperfermentasemia can range from moderate to pronounced (ALT levels from 4–5 to 10–25 ULN). However, the rate of fibrosis development is significantly lower than in adults; early progression of fibrosis is registered quite rarely (1–2.5%), and as a rule, this is detected in children with other compromising conditions, including liver diseases. Children may also develop "extrahepatic manifestations" of the disease: skin manifestations (telangiectasias, palmar erythema), lesions of other organs and systems, but they are registered significantly less frequently than in adults. The most frequent extrahepatic manifestation of CHB in children is kidney damage (glomerulonephritis) [3,5,7,12,46].

The course and outcomes of liver disease caused by HBV are largely determined by the relationship between the human immune system and the virus. As noted above, 5 phases are currently distinguished, which do not necessarily succeed each other sequentially, and differ in the presence of certain serological markers and blood biochemistry parameters (HBeAg, HBV DNA, ALT) [5,6,31]. A more detailed description of them is given below.

• Phase 1. HBeAg-positive chronic HBV infection — typical for perinatally infected individuals and associated with the detection of HBV with preserved specific T-cell function, at least until adulthood. Markers of this phase:

  • presence of HBeAg in blood serum;

  • very high level of HBV DNA;

  • stably normal ALT level (< 40 IU/L);

  • minimal necroinflammatory changes in liver tissue;

  • absence or slow progression of fibrosis;

  • high level of HBV DNA integration and clonal expansion of hepatocytes (this indicates the possible onset of hepatocarcinogenesis already in this phase of infection).

In this phase, the rate of spontaneous HBeAg clearance is very low. Patients are significantly infectious due to the high level of HBV DNA. A feature of childhood is the long persistence of this phase for many years, up to decades [12,31,48].

• Phase 2. HBeAg-positive chronic hepatitis B — characterized by:

  • presence of HBeAg in blood serum;

  • high level of HBV DNA;

  • elevated ALT level;

  • moderate or severe inflammatory process in the liver;

  • accelerated progression of fibrosis.

This phase may occur a few years after the first phase and more often and/or rapidly arises in individuals infected in adulthood. Its outcome varies: the majority of patients may achieve HBeAg-to-anti-HBe seroconversion and suppression of HBV DNA with transition to the HBeAg-negative infection phase; in other patients, control of HBV replication may be absent, and the process will progress to the HBeAg-negative CHB phase over many years [12,31].

• Phase 3. HBeAg-negative chronic HBV infection is characterized by:

  • absence of HBeAg in blood serum;

  • presence of anti-HBe;

  • undetectable or low (< 2000 IU/mL) level of HBV DNA;

  • normal ALT level.

The detection rate of this phase in childhood can reach 50%. However, some patients may have a VL above 2000 IU/mL (but usually < 20,000 IU/mL), with a persistently normal ALT level, minimal hepatic inflammatory activity, and minor fibrosis. These patients, if this phase persists, have a low risk of progression to cirrhosis or HCC, but progression to CHB may occur, which is usually observed in HBeAg-negative patients. Disappearance of HBsAg and/or its seroconversion to anti-HBs can occur spontaneously (1% of cases per year). As a rule, such patients have a low (< 1000 IU/mL) level of HBsAg in blood serum [12,31,49].

• Phase 4. HBeAg-negative chronic hepatitis B — characterized by:

  • absence of HBeAg in blood serum;

  • presence of anti-HBe;

  • constant or fluctuating, moderate or high serum HBV DNA levels (usually lower than in HBeAg-positive patients);

  • periodically or persistently elevated ALT levels;

  • necroinflammation and fibrosis according to liver tissue histology.

Most of these patients have HBV mutations in the pre-core and/or core promoter regions, which abolishes or minimizes HBeAg expression. This phase is associated with a low rate of spontaneous disease remission [12,31].

• Phase 5: HBsAg-negative phase (occult HBV infection), characterized by:

  • negative serum HBsAg (sometimes the absence of HBsAg may be related to the sensitivity of the assay used for its detection);

  • positive antibodies to HBcAg (anti-HBc) with or without detectable antibodies to HBsAg (anti-HBs);

  • normal ALT levels;

  • low or undetectable serum HBV DNA levels;

  • hepatitis B virus DNA (cccDNA) can often be detected in the liver.

Truly latent HBV infection can only be stated in the absence of serum HBsAg when determined by laboratory methods with a sensitivity of at least 0.01 IU/mL. The clinical significance of latent infection has not yet been definitively determined; isolated cases of occult hepatitis are registered in children. The oncogenic potential of this variant is being studied, along with its role in disease progression in patients with liver damage of another etiology (HCV, alcohol, etc.), as well as the possibility of virus transmission via blood transfusion or organ donation [9-13,22,30,45].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the disease/condition.

The definitive diagnosis of acute and chronic hepatitis B is established by comprehensive evaluation of epidemiological, clinical, biochemical, and serological data. To make a diagnosis, specific serological markers of HBV infection (HBsAg, anti-HBc IgM, anti-HBc, anti-HBs, HBeAg, anti-HBe) and HBV DNA should be detected.

Detection of hepatitis B surface antigen (HBsAg) in the patient's blood is used as a screening test, regardless of the presence or absence of a characteristic symptom complex and/or abnormalities in laboratory test results, because in addition to clinically manifest forms, a latent course of the disease is also possible. The criterion for differential diagnosis between acute and chronic hepatitis is the duration of the disease. If the disease duration is less than 6 months, the diagnosis is formulated as acute hepatitis B.

2.1 Complaints and Anamnesis

Comments: for young children, information about the presence of HBV infection in the mother is of primary importance.

Comments: if the disease is diagnosed in infants in their first year of life who had perinatal contact with hepatitis B, the fact of vaccination should not be decisive, as infection could have occurred in the prenatal period (before vaccination).

2.2 Physical Examination

Comments: hepatomegaly may be mildly expressed or be the only clinical sign of CHB. The younger the child, the more frequently splenomegaly is registered. The severity of hepatomegaly and splenomegaly correlates with the severity of the disease.

Comments: in children, darkening of urine and 'spotty' or acholic stools appear 1-2 days earlier than skin yellowing.

2.3 Laboratory Diagnostics

At the diagnosis stage

Comments: clinical blood count data (leukopenia, anemia, thrombocytopenia, signs of inflammatory reactions) allow for the timely detection of complications and emergency conditions developing in CHB.

Comments: when extrahepatic manifestations such as glomerulonephritis and tubulointerstitial nephritis develop, urinalysis findings (presence of leukocytes, protein, red blood cells, casts) indicate kidney or urinary system damage.

Comments: these test results allow for the assessment of disease activity and the severity of liver function impairment (cytolysis syndrome, cholestasis, and decreased protein-synthesizing function of the liver). A De Ritis ratio (AST:ALT ratio) > 1.0 indicates a prolonged inflammatory process in the liver.

Coagulogram data are necessary to assess the severity of the disease. A decrease in fibrinogen and PTI levels indicates impaired protein-synthesizing function of the liver (signs of hepatocellular insufficiency).

Comments: performed to confirm the etiological diagnosis and determine the phase of the process. To screen for asymptomatic forms, testing is performed to detect hepatitis B virus surface antigen (HBsAg) and antibodies to hepatitis B surface antigen (anti-HBs). Additional screening for class G antibodies to the hepatitis B virus core antigen (anti-HBc IgG) in the blood may also be performed for the differential diagnosis of past infection (positive anti-HBc / positive anti-HBs) versus post-vaccination immunity (negative anti-HBc / positive anti-HBs). Detection of anti-HBc antibodies also helps identify individuals with latent HBV infection. Testing for anti-HBc antibodies is particularly important for patients requiring immunosuppressive therapy, as HBV reactivation can occur in those with past HBV infection (positive anti-HBc / negative HBsAg).

Comments: performed in patients with severe chronic hepatitis B and the development of life-threatening complications.

At the examination stage during antiviral therapy (AVT):

Comments: performed to monitor the virological response to therapy and evaluate adverse events of systemic antiviral drugs. When using tenofovir** (in children aged 12 and older), creatinine levels should be monitored. Patients with decompensated cirrhosis and patients with renal impairment receiving #lamivudine** therapy should have their creatinine levels monitored more frequently (every one to three months).

Comments: performed to monitor the serological response to antiviral therapy and determine the phase of the process. If HBeAg seroconversion has occurred, repeat testing for HBeAg and anti-HBe is required to confirm the result.

Comments: performed to monitor the serological response to antiviral therapy. If HBsAg seroconversion occurs, repeat testing for HBsAg and anti-HBs is required to confirm the result. The appearance of anti-HBs accompanied by the clearance of HBsAg, e-antigen seroconversion [HBeAg(-)/anti-HBe(+)], and the absence of viral DNA in the blood indicate patient recovery. However, such cases are sporadic.

Comments: performed to assess treatment efficacy and the virological response to antiviral therapy, as well as to monitor for the development of drug resistance to #lamivudine**, #entecavir**, and tenofovir** (indicated from 12 years of age) every 3 months until the viral load in the blood becomes undetectable (at least on two consecutive visits). Once an undetectable viral load is achieved, this test is performed every 12 months.

At the stage of dispensary follow-up:

Comments: performed for the dynamic monitoring of indirect signs of chronic viral infection (lymphocytosis, ESR), hypersplenism (anemia, leukopenia, and thrombocytopenia), as well as erythrocyte and hemoglobin levels. The frequency of evaluation may be determined individually based on the clinical and biochemical picture of the disease, previous parameters, presence of liver cirrhosis, and comorbidities. The frequency is 1-2 times a year, depending on disease activity.

Comments: The frequency of evaluation may be determined individually based on the clinical and biochemical picture of the disease, previous parameters, presence of liver cirrhosis, and comorbidities. The frequency of examination is every 6 months for HBeAg-positive chronic hepatitis B; every 12 months for HBeAg-negative chronic hepatitis B with HBV DNA <2000 IU/mL; and every 6 months for the first year, then every 12 months, for HBeAg-negative chronic hepatitis B with HBV DNA >2000 IU/mL. Protein electrophoresis and coagulogram data are necessary to assess the severity of the disease. A decrease in total protein, albumin, fibrinogen, and prothrombin index (PTI) indicates impaired protein-synthetic function of the liver (signs of hepatocellular insufficiency). A significant increase in total protein, beta- and gamma-globulin concentrations indicates the development of mesenchymal-inflammatory syndrome and the activation of autoimmune reactions. The frequency of evaluation for inactive CHB is every 6-12 months, depending on disease activity and severity.

Comments: HBsAg testing is performed to rule out spontaneous (or treatment-induced) HBsAg clearance and, in the event of HBsAg loss, to monitor anti-HBs levels annually. HBeAg testing is performed once; if HBe-negative CHB is diagnosed after the initial evaluation, the test is repeated in the event of an enzymatic flare. In cases of HBeAg-positive CHB, testing for HBeAg and anti-HBe is performed every 3–6 months. If HBeAg/anti-HBe seroconversion is achieved as a result of treatment, subsequent HBeAg monitoring is performed only if there is a relapse of viremia and an enzymatic flare [51,31,48,70,72].

Comment: if qualitative PCR was performed prior to quantitative PCR and HBV DNA was not detected in the patient's blood, the quantitative analysis is not performed if the qualitative result is negative.

Comments: performed in patients with CHB and advanced fibrosis or liver cirrhosis (F3-4). During dispensary follow-up, monitoring alpha-fetoprotein (AFP) levels and performing a comprehensive ultrasound examination of the abdominal organs once a year allows for the timely detection of HCC development.

2.4 Instrumental Diagnostics

At the diagnostic stage:

Comments: comprehensive abdominal ultrasound is used to clarify the size and structure of the liver, spleen, pancreas, and lymph nodes, identify increased vessel diameter, and detect the presence or absence of effusion in order to diagnose space-occupying lesions and rule out concomitant gastrointestinal pathology, which in some cases can be decisive in determining the disease stage and treatment tactics. Patients with unclear focal changes in the liver and spleen or indefinite, contradictory ultrasound findings require in-depth instrumental examination.

Comments: the diagnostic accuracy of liver elastography and laboratory blood tests assessing hepatic inflammation and fibrosis based on a panel of serum biomarkers for non-invasive staging of liver fibrosis has been proven. Combining liver elastography and laboratory tests increases the accuracy of fibrosis staging. The frequency of liver elastography depends on the phase of the infectious process: in HBeAg-positive CHB, once a year; in HBeAg-negative CHB with HBV DNA less than 2000 IU/mL and HBV infection, once every 2 years; with HBV DNA greater than 2000 IU/mL, once a year.

Comments: one of the manifestations of portal hypertension is esophageal varices. Endoscopic examination is performed to detect esophageal varices, determine their grade, and apply clips or bands in the event of bleeding or for the prevention of hemorrhage from dilated esophageal veins in patients with liver cirrhosis.

Comments: contrast-enhanced CT or MRI of the abdominal organs has high informativeness in detecting small neoplasms. It is performed for early detection and differential diagnosis of focal liver lesions (hepatocellular carcinoma, metastatic tumors, angiomas, adenomas, cysts).

At the stage of dispensary follow-up:

Comments: comprehensive ultrasound of the abdominal organs and retroperitoneal space is performed to evaluate the efficacy of pathogenetic therapy, detect changes in the size and structure of the liver and spleen, monitor vascular diameter changes, and check for fluid in the abdominal cavity.

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

2.5 Other Procedures

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

Medical therapy for CHB includes baseline (lifestyle, diet), etiotropic (antiviral), pathogenetic, and symptomatic therapy.

Diet and Lifestyle

Lifestyle is a critical factor in maintaining the compensation of liver function. Patients with chronic hepatitis outside of exacerbations require a modified lifestyle with restrictions on physical and emotional overexertion. During an exacerbation, bed rest at home with a midday rest period is indicated, which creates more favorable conditions for liver function by increasing hepatic blood flow in the horizontal position and eliminating physical and mental stress.

Adherence to a special diet is not required in uncomplicated chronic hepatitis B; however, a burdened premorbid background such as metabolic syndrome and hepatic steatosis associated with excessive fat and cholesterol in the diet contributes to the progression of pathological processes in the liver [4,31,46,48,70]. Poorly absorbed disaccharides and soluble dietary fibers affect nitrogen metabolism in the colon and are useful in the management of patients with liver failure.

Children with an asymptomatic course of the disease and a normal ALT level (immune-tolerant phase / chronic HBV infection, HBeAg-positive, and inactive carrier phase / chronic HBV infection, HBeAg-negative) do not require strict adherence to a regimen and diet. They are prescribed a general regimen allowing physical education classes and the standard basic diet (OBD). Children in the immune clearance phase (chronic hepatitis B, HBeAg-positive) and the reactivation phase (chronic hepatitis B, HBeAg-negative) require a gentle regimen with restriction of physical activity (sports, participation in competitions). Alcohol in any form is strictly prohibited! [4,31,46,48,70,103].

Mild ascites causing minimal discomfort and difficulty in movement and breathing does not require special treatment in most cases. In more cases, the treatment regimen includes, in addition to drug therapy, salt restriction to 1–2 mmol/kg per day. Prolonged salt and fluid restriction can lead to growth retardation in children and should be compensated for by increasing the energy value of the diet [4,31,46,48,70,103].

3.1 Conservative Treatment

Antiviral therapy:

The goal of etiotropic therapy is effective and sustained suppression of HBV replication, which prevents disease progression, reduces the risk of severe complications (cirrhosis, HCC) and extrahepatic manifestations, and improves the quality and life expectancy of the patient [1-8,12,31,39,46,48,50,51,145]. The main factors influencing the choice of antiviral therapy (AVT) tactics are: presence/absence of HBeAg in the blood; cytolytic activity; degree of fibrosis; viremia level; patient age; presence and nature of complications [31,48,70,71].

Considering the features of the pathogenesis of this infection, including the possibility of viral DNA integration into the human genome, achieving complete HBV eradication as a result of ongoing AVT is rarely successful, and its final duration is not defined; lifelong drug intake is possible [1,12]. In children, CHB is usually asymptomatic, and in most cases, young children do not require treatment. Therefore, prescribing etiotropic therapy to children and adolescents should be approached with caution and strictly in the presence of indications [31,46,48,70,145].

• Indications for AVT in children and adolescents with chronic hepatitis B: [31,48,70,71,145]:

  • Virological and/or serological activity of hepatitis indicating pronounced viral replication (HBeAg (+) positive and HBV DNA > 2000 IU/ml);

  • Pathological activity of the process determined by pathomorphological examination of liver biopsy (surgical) material using histochemical methods or by blood ALT and AST levels (biochemical criteria – ALT > 1.5–2 ULN for at least 6 months);

  • Liver fibrosis equal to or greater than F2 on the METAVIR scale (regardless of ALT level, HBV DNA, and HBeAg absence);

  • Regardless of the degree of fibrosis, biochemical and virological activity in the case of: coinfection (HIV, HDV) or a burdened family history of cirrhosis or liver cancer, or an immunosuppressive state, or extrahepatic manifestations (glomerulonephritis or vasculitis), or comorbid pathology (non-alcoholic fatty liver disease or other progressive chronic liver diseases, diabetes mellitus, etc.);

  • Absence of contraindications to the systemic antiviral drugs used.

Comments: daily dose of the drug is 3 mg/kg of body weight (maximum 100 mg/day) once a day, course duration 48–72 weeks. Due to high rates of resistance development, the use of #lamivudine** should be considered only as an alternative systemic antiviral drug when there are indications to start therapy and drugs with a high resistance profile are contraindicated or unavailable [31,46,74,98,99,102,121,122,145].

Comments: the dosage of #entecavir** is based on body weight. For treatment-naive patients, doses are 0.015 mg/kg once daily for children weighing 10–30 kg and increase to a maximum dose of 0.5 mg once daily for children weighing more than 30 kg. Course duration 72–96 weeks [128,140,145].

Antiviral therapy is usually continued for an indefinite period for most patients who do not achieve seroconversion. For patients who achieve seroconversion, treatment is usually continued for one year after seroconversion [128,129,145]. The ideal efficacy endpoint is sustained disappearance of HBsAg after the end of therapy with or without the appearance of anti-HBs. This is associated with complete remission of CHB and a favorable long-term prognosis. Satisfactory efficacy is defined as achieving a sustained virological and biochemical response with sustained HBeAg seroconversion persisting after therapy withdrawal (in both initially HBeAg (+) positive and initially HBeAg (-) negative patients). This outcome is also associated with a favorable prognosis. Resistance to NRTIs is characterized by the selection of HBV variants with amino acid substitutions providing reduced sensitivity to the drug used. It can lead to primary non-response or virological relapse [72,145].

The duration of therapy in children has not been definitively determined, but at present it is possible for up to 3 years.

Pathogenetic and symptomatic therapy:

Comments: infusion therapy for the purpose of rehydration, detoxification, and correction of water-electrolyte balance is carried out using intravenous solutions: electrolyte solutions, electrolytes in combination with carbohydrates (complex sodium chloride solution** (potassium chloride + calcium chloride + sodium chloride), potassium chloride + sodium acetate + sodium chloride**, potassium acetate + calcium acetate + magnesium acetate + sodium acetate + sodium chloride**), correction of carbohydrate metabolism in patients with cytolytic activity and liver function disorders (taking into account the age of children and indications).

Comments: the use of other drugs for the treatment of liver diseases is acceptable.

Comments: 10 mg/kg/day orally. For children under 3 years of age in the form of a suspension, for children over 3 years old – suspension or capsules.

For patients with chronic hepatitis B and advanced stages of liver fibrosis:

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 presence of protein-free edema and ascites. Albumin plays an important role in maintaining intravascular oncotic pressure. In patients with hypoalbuminemia, the administration of human albumin** combined with diuretics promotes the resolution of ascites, reduces ascites recurrence, lowers the frequency of complications, and improves prognosis [130,142,143].

3.1.2 Symptomatic therapy

Administered depending on the symptoms of concomitant diseases/conditions.

3.2 Surgical Treatment

Comment: endoscopic variceal ligation is performed both for the prevention of bleeding and for its control.

Comments: in milder cases with non- tense ascites, conservative therapy is sufficient. In patients with liver cirrhosis and tense ascites, human albumin** should be administered after paracentesis at a dose of 8 g per each liter of ascitic fluid removed to prevent circulatory disorders. To prevent complications following paracentesis, volume replacement is necessary. Only a 20% human albumin** solution should be prescribed.

3.3 Other Treatment

Comments: indications for extracorporeal methods include prominent cholestasis, bilirubin levels exceeding 300 µmol/L, and signs of hepatic encephalopathy with symptoms of incipient cerebral edema and seizure activity. Contraindications include severe blood coagulation disorders and disseminated intravascular coagulation (DIC) syndrome.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specialized rehabilitation measures have not been developed for patients with CHB.

A diagnosis of CHB is not a contraindication for sanatorium-resort treatment.

5. Prevention and Dispensary Observation

5.1 Prevention

Prevention of HB is carried out in accordance with Sanitary and Epidemiological Rules SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" and includes a set of measures aimed at the source of infection, interrupting transmission routes, and increasing population resistance to the virus.

Quarantine and isolation measures for contacts in the focus of a CHB patient are not conducted. However, contact screening is performed with ALT determination, HBsAg, anti-HBs, followed by screening in children every 2 months for 6 months, and in adults after 6 months. Individuals in whom anti-HBs are detected in protective titers during the initial examination do not require further follow-up (past HBV infection or vaccinated against HBV) [79].

5.1.1 Specific prevention

The leading measure in the prevention of hepatitis is active and passive immunization of the population.

Comments: active immunization of the population against hepatitis B is carried out in accordance with the National Immunization Schedule, the Immunization Schedule by Epidemiological Indications, and instructions for the use of immunobiological medicinal products. Both monoproducts for hepatitis B prevention and combination antiviral and antibacterial vaccines are registered in the Russian Federation. All vaccines registered in the Russian Federation are interchangeable and can be administered simultaneously with vaccines against other infections. The primary immunization schedule is the intramuscular administration of three vaccine doses at intervals of 0–1–6 months (dose 1 at the start of vaccination [the first day of a child's life], dose 2 one month after the first vaccination, dose 3 six months from the start of vaccination). For unvaccinated patients scheduled for surgical interventions, emergency vaccination is performed according to the 0–7–21 day schedule with a booster dose 12 months after the start of vaccination.

Post-vaccination immunity persists for approximately 20 years.

Comments: for children belonging to risk groups (born to mothers who are HBsAg carriers, have HB, or had viral hepatitis B in the third trimester of pregnancy, or whose test results for hepatitis B markers are unavailable, or who use narcotic drugs or psychotropic substances), vaccination against HB is performed according to the 0–1–2–12 month schedule (dose 1 at the start of vaccination, dose 2 one month after the first vaccination, dose 2 [sic] two months from the start of vaccination, dose 3 12 months from the start of vaccination).

Passive immunization using Hepatitis B Human Immunoglobulin for the prevention of HB is carried out in newborns born to HBV-infected and HBsAg-carrier mothers. The first 24 hours of life are considered the most desirable time for prevention. The drug is administered simultaneously with the vaccine for the prevention of viral hepatitis B** at different anatomical sites. For passive immunization of children born to HBV-carrier mothers, a single dose of 2 mL (100 IU) of Hepatitis B Human Immunoglobulin is required.

Comments: emergency prevention of HB is performed in cases of injury with medical instruments (as well as instruments used for manicure, piercing, tattooing) used when working with individuals infected with HB, or after contact of mucous membranes with infected biological fluids (blood, serum, plasma, urine, saliva); unprotected sexual intercourse with an individual infected with HBV; intravenous drug use; and in previously unvaccinated individuals scheduled for surgical interventions and/or belonging to high-risk groups (patients in hemodialysis centers, patients receiving frequent blood and blood component transfusions for life-saving reasons, etc.).

The emergency vaccination schedule is 0–7–21 days with revaccination with the viral hepatitis B vaccine** 12 months after the start of vaccination; an alternative schedule can be 0–1–2–12 months. The viral hepatitis B vaccine** is used either combined with Hepatitis B Human Immunoglobulin or without it.

The most desirable time for emergency prevention is the first 24–48 hours after contact with HBV infection has occurred (up to 15 days, although the effectiveness of prevention drops sharply by then), or prior to the start of procedures (hemodialysis, blood transfusion, elective surgery, etc.).

Hepatitis B Human Immunoglobulin is administered to children under 10 years of age who have been exposed to the risk of infection at a dose of 100 IU; for children over 10 years of age and adults, the drug is administered at 8–12 IU/kg of body weight.

5.1.2 Nonspecific prevention

5.2 Dispensary monitoring

All children with chronic hepatitis B (CHB) are subject to clinical follow-up (dispensary observation) until the age of 18; further management recommendations are in accordance with clinical guidelines for the treatment of CHB in adult patients. The frequency of examinations is at least once a year, and may be increased if the disease is active or during antiviral therapy. This section presents a summary of recommendations for examination as part of clinical follow-up; more details can be found in the relevant subsections of the "Examination" section.

Comments: the frequency of clinical follow-up and the scope of laboratory and instrumental examinations depend on clinical and laboratory parameters (the phase of CHB) and the therapy received by the patient (See the Treatment section).

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 medical care, including high-tech medical care.

Medical care for children with CHB can be provided in the following settings:

• 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 care in infectious disease departments providing round-the-clock medical observation and treatment, and, when indicated, in an anesthesiology, resuscitation, and intensive care unit 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 or general practitioner (family physician) in an outpatient setting.

Primary specialized health care is provided by an infectious disease specialist in an outpatient medical organization (pediatric infectious diseases office in a children's polyclinic).

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

Indications for hospitalization in a medical organization:

1. Emergency care: acute deterioration of the general condition of a CHB patient, onset of jaundice, abdominal pain, headache with impaired consciousness [5,6,31,73].

2. Routine (elective) care: diagnostic procedures at the diagnostic stage, pathomorphological examination of liver biopsy (surgical) specimens using immunohistochemical methods (if necessary), initiation of antiviral therapy and management of significant adverse events resulting from it, deterioration of hematological and biochemical parameters, exacerbation of chronic diseases, development of extrahepatic manifestations of CHB, and decompensation of liver cirrhosis (signs of hemorrhagic syndrome, peripheral edema, ascites) [5,6,31,73].

7. Additional Information

Factors that increase the risk of liver failure and death:

• co-infection with hepatotropic viruses and human immunodeficiency virus; comorbid conditions such as peptic ulcer disease, diabetes mellitus, blood disorders;

• infections: odontogenic, tonsillogenic, tuberculosis;

• alcoholism, drug addiction, and substance abuse;

• drug-induced toxic hepatitis;

• immunodeficiency states;

• protein-energy malnutrition, unbalanced diet;

• liver transplantation [5,6,23,67,77,78,82,83,84,85,86,87,88,89].

Factors that negatively affect the outcome of antiviral therapy:

• occurrence of adverse events requiring a dose reduction of systemic antiviral drugs;

• non-adherence by the patient to the systemic antiviral drug regimen;

• occurrence of adverse events requiring medical correction or interruption of the AVT course [6,23,64,67,68,77,78,83,84,85,86,87,88,89].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

The clinical guidelines "Chronic Viral Hepatitis B in Children" were developed by members of the Euro-Asian Association of Infectious Diseases (EAAID).

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of the clinical guidelines:

1. Infectious disease specialist;

2. Pediatrician;

3. General practitioner (family physician);

4. Gastroenterologist;

5. Medical students, residents, postgraduate students.

6. 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 evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on 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:

• Federal Law No. 157-FZ dated September 17, 1998, "On Immunoprophylaxis of Infectious Diseases".

• Federal Law No. 326-FZ dated November 29, 2010, "On Compulsory Medical Insurance in the Russian Federation".

• Federal Law No. 323-FZ dated November 21, 2011, "The Fundamentals of Healthcare Protection in the Russian Federation".

• Order of the Ministry of Health and Social Development of Russia No. 494 dated August 9, 2005, "On the Procedure for the Use of Medicinal Products in Patients for Vital Indications".

• Order of the Ministry of Health of Russia No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services".

• Order of the Ministry of Health of Russia No. 1122n dated December 6, 2021, "On Approval of the National Calendar of Preventive Vaccinations, Calendar of Preventive Vaccinations for Epidemic Indications, and the Procedure for Conducting Preventive Vaccinations" (Registered with the Ministry of Justice of Russia on December 20, 2021, No. 66435).

• Order of the Ministry of Health of Russia No. 205n dated May 2, 2023, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers" (Registered with the Ministry of Justice of Russia on June 1, 2023, No. 73664).

• Order of the Ministry of Health of Russia No. 700n dated October 7, 2015, "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).

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

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

• Order of the Ministry of Health and Social Development of Russia No. 521n dated May 5, 2012, "On Approval of the Procedure for Providing Medical Care to Children with Infectious Diseases" (Registered with the Ministry of Justice of Russia on July 10, 2012, No. 24867).

• Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020, "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).

Differential diagnosis of CHB

Differential diagnosis of CHB is carried out with chronic viral hepatitis C, autoimmune hepatitis (AIH), drug-induced liver injury, and metabolic disorders (Wilson's disease, glycogenoses, alpha-1 antitrypsin deficiency, etc.).

• Chronic viral hepatitis C (CHC)

As a rule, the course of chronic hepatitis C in childhood is smooth and paucisymptomatic. Hepatomegaly is often the only symptom of the disease. In some cases, non-specific symptoms such as headache, abdominal pain, nausea, vomiting, unstable stool, loss of appetite, and arthralgia are observed. Extrahepatic manifestations (autoimmune thyroiditis, cryoglobulinemia, membranoproliferative glomerulonephritis) are extremely rare in childhood. Given the similar clinical symptoms, differential diagnosis is based on the results of serological testing (detection of anti-HCV antibodies) [61, 62, 63].

• Autoimmune hepatitis

is a chronic immune-mediated liver disease characterized by the development of inflammation, fibrosis, and, in some cases, liver failure. The spectrum of clinical manifestations of AIH is diverse—ranging from the absence of overt manifestations of liver damage to an acute and even fulminant course of hepatitis. When examining any patient with acute or chronic liver disease, especially in the presence of hypergammaglobulinemia, as well as if the patient has other manifestations of autoimmune diseases, a blood serum test for the autoimmune liver panel (determination of ANA, ASMA, anti-LKM-1, anti-SLA/LP, ANCA autoantibodies) should be performed [53, 54, 55].

• Drug-induced liver injury

They usually occur in individuals with hypersensitivity to these drugs, which is due to individual human genetic characteristics. They can be caused by many medications, but most often occur when a drug is prescribed for a long time and in high doses. More than half of drug-induced hepatitis cases are associated with the long-term use of anti-tuberculosis drugs. Both acute and chronic liver damage can develop. When examining patients with chronic hepatitis of unclear etiology, 10% of cases of laboratory parameter changes can be associated with medication intake. DILI has no pathognomonic signs. The key moment in establishing the diagnosis is a detailed drug history and a positive effect after withdrawing the suspected agent. Suspicion of DILI may arise if ALT increases by 4 times or more, and jaundice appears in the patient within 3 months from the start of drug administration [56, 57].

• Metabolic liver diseases (in congenital and hereditary diseases, hemosiderosis, glycogenosis, lipidosis, galactosemia, hepatolenticular degeneration, alpha-1 antitrypsin deficiency, etc.)

These diseases manifest in childhood and, in addition to persistent hepatomegaly and jaundice, present with severe gastrointestinal, central nervous system, and other organ and system disorders. Cytolysis in these conditions is usually mildly expressed, and morphological studies indicate dystrophic changes in hepatocytes and fatty liver disease. The decisive factor in diagnosis is the detection of various enzymatic disorders that act as triggers in the development of these diseases. Thus, it is necessary to determine the level of ceruloplasmin in Wilson's disease, alpha-1 antitrypsin in alpha-1 antitrypsin deficiency, glucose-6-phosphatase and glycogen in glycogen storage disease, galactokinase in galactosemia, iron in hemosiderosis, and other parameters depending on the differential diagnosis being performed [58, 59, 60].

Appendix B. Physician Action Algorithms

All children with CHB

Appendix C. Patient Information

Chronic viral hepatitis B is a liver disease caused by the hepatitis B virus. According to WHO data, about 2 billion people worldwide are infected with HBV, more than 400 million people have a chronic infection, and more than 600,000 people die annually from complications of hepatitis B. Clinical manifestations of hepatitis B vary from mild and asymptomatic forms of the disease to severe cases that frequently end in the development of chronic hepatitis B, liver cirrhosis, and fatal hepatocellular carcinoma.

The source of infection is a sick person or a carrier of this virus. Most infected individuals, who serve as a permanent reservoir of the virus, do not suspect that they are ill and therefore do not take any precautions.

The route of transmission is parenteral (when virus-infected blood enters the bloodstream of a susceptible person). Currently, the most common non-medical parenteral route is infection through intravenous drug use. However, other household routes of transmission are also possible—blood-to-blood contact (via toothbrushes, hairbrushes, razors, and other hairdressing and cosmetic tools, during piercing and tattooing), as well as sexual and perinatal transmission from an ill mother to her child (during childbirth, less frequently during newborn care, and extremely rarely in utero). The medical parenteral route occurs in medical facilities during blood and plasma transfusions, or when using infected (poorly sterilized) medical instruments during examinations, dental treatments, and other medical procedures.

The incubation period for hepatitis B lasts from several weeks to 6 months. The screening method for confirming the diagnosis is the detection of the surface antigen—HBsAg. Chronic infection is characterized by its persistence for at least six months (with or without the simultaneous presence of HBeAg). The likelihood of chronicity of viral hepatitis B depends on the age of the child at the time of infection. Chronic forms develop most frequently when children are infected under 6 years of age (the rate of chronicity of hepatitis B in infants reaches up to 90%).

Medical treatment may be prescribed for chronic hepatitis B.

Treatment helps slow down the progression of liver cirrhosis, reduce the incidence of hepatocellular carcinoma, and improve long-term survival rates in patients. Before, during, and after antiviral therapy, monitoring of parameters is necessary (clinical and biochemical parameters, serological markers, viral load, invasive and non-invasive methods for assessing liver fibrosis).

Active immunization is a radical solution to the problem of preventing hepatitis B, hepatitis D, and hepatocellular carcinoma. Vaccination against hepatitis B is included in the national immunization schedule and is administered to all children 3 times starting from birth. Vaccination provides protection against hepatitis B for 7–10 years or more.

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

Appendix H1. METAVIR scoring system for assessing the degree of liver fibrosis (Meta-analysis of histological data in viral hepatitis)

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.

Assessment tool: scale.

Content and scoring:

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

F0 – less than 6.2 kPa – no fibrosis

F1 – 6.2–8.3 kPa – minimal fibrotic liver changes. Portal tract expansion without septum formation

F2 – 8.3–10.8 kPa – moderate fibrotic liver changes. Portal tract expansion with solitary portoportal septa

F3 – 10.8–14 kPa – severe fibrotic liver changes. Numerous portocentral septa without cirrhosis

F4 – greater than 14 kPa – liver cirrhosis

Appendix G2. Child-Pugh score

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 liver failure.

Assessment tool: scale.

Content and scoring:

Comments:

Assessment of the degree of hepatic encephalopathy:

• Absent (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

The severity of liver cirrhosis is evaluated using a scoring system calculated based on 5 or 6 parameters. There are three classes in total: 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

Appendix G3. Calculation of the APRI fibrosis index

Title: Calculation of the APRI fibrosis index.

Source: Yen Y. H. et al. APRI and FIB-4 in the evaluation of liver fibrosis in chronic hepatitis C patients stratified by AST level //PloS one. – 2018. – Vol. 13. – No. 6. – P. e0199760.

Type: index.

Content: Calculation formula:

APRI = (AST / (ULN AST)) * 100 / platelets (10⁹/L)

AST – patient's aspartate aminotransferase value, ULN AST – upper limit of normal for AST, Platelets (10⁹/L) – patient's platelet count per 1 L of blood

Key (interpretation):

Appendix G4. Calculation of the FIB-4 fibrosis index

Title: Calculation of the FIB-4 fibrosis index.

Source: Yen Y. H. et al. APRI and FIB-4 in the evaluation of liver fibrosis in chronic hepatitis C patients stratified by AST level //PloS one. – 2018. – Vol. 13. – No. 6. – P. e0199760.

Type: index.

Content: Calculation formula:

FIB-4 = Age (years) * AST / platelets (10⁹/L) * √ALT

Age – patient's age (years)

AST – patient's aspartate aminotransferase value

Platelets (10⁹/L) – patient's platelet count per 1 L of blood

√ALT – square root of the patient's ALT value

Key (interpretation):

Appendix G5. 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 liver damage.

Assessment tool: index.

Content and scoring:

0 = no activity

1-4 = minimal activity

5-8 = low activity

9-12 = moderate activity

13-18 = high activity