Chronic viral hepatitis B: clinical guidelines

List of Abbreviations

CD4 - cluster of differentiation 4 molecule

HAV - hepatitis A virus

HBcAg - hepatitis B core antigen

HBeAg - hepatitis B e antigen

HBsAg - hepatitis B surface antigen

HBV - hepatitis B virus

HCV - hepatitis C virus

HDV - hepatitis D virus

ALT - alanine aminotransferase

AST - aspartate aminotransferase

Viral load - viral load

HIV - human immunodeficiency virus

GGT - gamma-glutamyl transferase

HCC - hepatocellular carcinoma

DNA - deoxyribonucleic acid

cccDNA - covalently closed circular DNA

CT — computed tomography

IU - international unit

MRI — magnetic resonance imaging

NAs - nucleoside and nucleotide reverse transcriptase inhibitors

PT - prothrombin index

RNA - ribonucleic acid

eGFR – estimated glomerular filtration rate

TAF** – tenofovir alafenamide**

TDF** – tenofovir**

Ultrasound — ultrasound examination

CHB - chronic viral hepatitis B

LC – liver cirrhosis

ALP - alkaline phosphatase

Terms and Definitions

Biochemical response – normalization of blood ALT activity.

Viral load – amount of viral DNA in the blood.

Virological breakthrough – a 10-fold increase in serum viral load from its nadir achieved during treatment in a patient with an initial virological response.

Viral suppression (virological response to NA treatment) – undetectable blood HBV DNA level.

Hepatitis – inflammation of the liver, defined by elevated blood ALT activity and/or the presence of necroinflammatory changes in a liver biopsy specimen.

Histological response – a decrease in necroinflammatory activity by at least 2 points on histological activity scales of hepatitis without an increase in fibrosis.

Dual prophylaxis – administration of human hepatitis B immunoglobulin and hepatitis B vaccine** to newborns of HBsAg-positive mothers to prevent perinatal transmission.

Non-response – a decrease in HBV DNA viral load by less than 1 log_{10 (}less than 10-fold) from baseline after 3 months of NA therapy

Complete response – absence of cccDNA based on PCR analysis of a liver biopsy (not assessed in routine clinical practice).

Sterilizing response – disappearance of integrated HBV DNA from the genome (not assessed in routine clinical practice).

Seroconversion – disappearance of HBsAg from the blood and appearance of antibodies against it.

Seroreversion – reappearance of HBsAg in the blood following previously achieved seroconversion.

Stopping rules – criteria for discontinuing therapy.

Functional response – sustained HBsAg clearance with or without HBs seroconversion and undetectable blood HBV DNA following a course of treatment.

Cytopathic effect – death or other damage to virus-infected cells.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic hepatitis B virus (HBV) infection can present either with the development of inflammation in the liver tissue (hepatitis) or without signs of necroinflammatory changes. Therefore, the current international classification uses two terms: chronic HBV infection, in the absence of clinical and laboratory signs of necroinflammatory changes in the liver tissue, and chronic hepatitis B (CHB), in their presence [1]. Considering that these conditions are phases of a single pathological process, statistical nomenclature uses the term CHB [2].

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

The causative agent of CHB is HBV, which is a small hepatotropic DNA virus belonging to the Hepadnaviridae family. Externally, it is covered by a lipid envelope embedded with HBsAg (HBV surface antigen). The envelope surrounds a core (nucleocapsid) comprising HBcAg (HBV core antigen). Inside the nucleocapsid are the viral polymerase and the viral genome, the feature of which is that it is represented by a double-stranded DNA, with one strand shorter than the other [3–5].

HBV is capable of integrating into the human genome, which determines its prolonged persistence and hinders the eradication of this infectious agent. Humans are the only natural host for HBV [3–5]. In the human body, HBV first attaches nonspecifically to heparan sulfate on the hepatocyte cell membrane, after which conditions are created for the interaction of HBsAg with the hepatocyte transmembrane protein NTCP (sodium-taurocholate cotransporting polypeptide), which serves as the receptor for the virus, determining its hepatotropism. This is followed by virus endocytosis [8–11]. The endosomal membrane fuses with the viral envelope, releasing the nucleocapsid into the cytosol, which is then transported by the hepatocyte microtubule motor system to its nucleus. There, the nucleocapsid releases the viral DNA, and the covalently linked viral polymerase dissociates from it. It extends the shorter DNA strand of the virus and covalently closes both strands, forming covalently closed circular DNA (cccDNA), which serves as a template for the production of viral proteins and pregenomic RNA. CccDNA is coated with histones and non-histone proteins, becoming a kind of additional microchromosome in the hepatocyte nucleus, where there may be several dozen copies of it. CccDNA is highly stable and can persist for a long time, also ensuring the persistence of infection [12].

Part of the viral DNA molecules integrates into the hepatocyte chromosomes as integrated DNA, which may contribute to carcinogenesis.

Hepatocyte RNA polymerase II transcribes the mRNAs of HBV proteins as well as the pregenomic RNA of the virus, which are transported to the hepatocyte cytoplasm, where the viral pregenomic RNA binds to the viral polymerase and HBcAg, forming an immature nucleocapsid. Inside the immature nucleocapsid, the viral polymerase first forms a full (-) DNA strand using the pregenomic RNA template, and then, using the latter as a template, forms an incomplete (+) DNA strand, thus producing a mature capsid that returns to the nucleus to replenish the pool of viral cccDNA or is sent to the endoplasmic reticulum to acquire a lipid envelope with HBsAg and leave the cell [13]. At the same time, HBsAg is produced in great excess, and its molecules form aggregates that are also partially released into the blood.

HBsAg, in the form of these aggregates and as a component of the viral envelope, is present in the blood of patients from the first weeks of infection (a few weeks before the appearance of clinical and biochemical signs of the disease) and until complete suppression of viral genome transcription. In a favorable course of acute hepatitis B, this is observed for no more than 6 months of the disease. If HBsAg persists in the blood for more than 6 months, it indicates the development of chronic HBV infection [14].

Unlike HBsAg, HBcAg is not secreted by hepatocytes and is virtually absent in the blood of patients; however, the body produces antibodies against this antigen. Anti-HBc are the very first antibodies formed in response to HBV infection: they can be detected starting from the first month after the appearance of HBsAg in the blood. Unlike antibodies against other viral antigens (HBsAg and HBeAg), they are produced, as a rule, in all patients. Since the hepatitis B vaccine** contains only HBsAg, its administration elicits only anti-HBs antibodies. HBV infection is almost always accompanied by the formation of anti-HBc, which are not produced in response to vaccination, and these antibodies persist in the blood for many years even after the elimination of HBsAg and viral DNA from the blood; therefore, the presence of these antibodies in the blood is a reliable marker of a previous encounter with HBV. In the absence of a sterilizing response, reactivation of HBV infection can occur upon the development of acquired immunodeficiency or drug-induced immunosuppression, which dictates the need to screen such patients for anti-HBc [14, 110, 159].

In addition to structural proteins, the viral genome also encodes the secretory antigen HBeAg, the precise function of which has not yet been established, but it has been shown that its blood level is an indicator of viral genome replication activity. The elimination of this antigen from the blood, especially followed by the appearance of anti-HBe (HBe seroconversion), is an indicator of decreased viral activity and patient infectivity [14].

There are 10 genotypes of HBV (A–J), differing in genome sequence by 8% or more. Genotypes A and D are widespread in Africa, Europe, Russia, and India, while genotypes B and C are prevalent in Asia [1,5].

CHB caused by genotypes C and D has a higher risk of progression than that caused genotype A [15]. The rate of remission following HBeAg seroconversion, as well as spontaneous HBsAg clearance, is higher in patients with genotype A compared to genotypes C and D [16–17, 136]. The response to interferon therapy depends on the genotype, unlike the response to direct-acting antiviral drugs (nucleoside and nucleotide reverse transcriptase inhibitors; see 3.3).

Since viral polymerase frequently makes errors when generating the genome of new virions, the virus mutates quite actively, and over time, several genetically distinct quasispecies of the pathogen emerge within an infected individual [18, 143, 167].

The virus itself does not exert a cytopathic effect, and hepatocyte damage during infection is primarily caused not by the virus per se, but by the immune system's reaction to it. Depending on its severity, the following outcomes of HBV infection are possible. If the response is adequate and timely, clearance of viruses circulating in the blood occurs, along with suppression of their replication in hepatocytes, leading to recovery after acute infection. If the immune response is excessively pronounced and/or untimely, it leads to massive hepatocyte death and the development of acute fulminant hepatitis B, quite often with a fatal outcome [135]. In cases of delayed or inadequate immune response, partly due to the depletion of NK-cell function, the infection becomes chronic [14, 137].

1.3 Epidemiology of the Disease or Condition

According to WHO estimates, there were 296 million people with chronic hepatitis B worldwide in 2019 [19]. Currently, due to the active implementation of vaccination, a certain decrease in incidence is observed [20].

The incidence of CHB in the territory of the Russian Federation in 2000–2009 stabilized at 14.0–16.0 per 100,000 population. Since 2010, a downward trend in the incidence of CHB has been observed in the Russian Federation. In 2018, 13,615 new cases of CHB were detected, with an incidence rate of 9.28 per 100,000 population. In 2019, the incidence of CHB in Russia decreased significantly to 8.6 per 100,000 population. There is a potential impact of the COVID-19 pandemic on the CHB incidence rate due to underdetection of new cases: for instance, in 2020 and 2021, the incidence of CHB was 4.36 and 5.1 per 100,000 population, respectively, while in 2022 this figure was 8.3 per 100,000 population. In 2023, the incidence rate was 8.4 per 100,000 population. The epidemic process, manifested by chronic forms of infection, plays a leading role in maintaining the continuity of the process. In some regions, the incidence of CHB approaches 1,000 per 100,000, i.e., about 1% of the total population. The highest levels are observed in the most socially active age group of 30–39 years [21].

HBV is quite stable in the external environment: at room temperature it persists for 3 months, in a refrigerator for 6 months, and in dried plasma for 25 years [22].

The source of infection is humans. Although the virus can be detected in almost all biological fluids of an infected person, only blood and semen pose a real epidemiological danger. Under natural conditions, the infection is transmitted sexually, via household contact of wounds with infected blood, and vertically, predominantly during childbirth [14].

The infectious dose of the pathogen is very small, so transmission is possible via micro-droplets of blood invisible to the naked eye that get onto microscopic wounds of the skin and mucous membranes, for example, when sharing combs, washcloths, and other personal care items.

During vaginal sex, the main risk factor is trauma to the female genital tract and male genitalia. Since the rectum is not adapted for sexual intercourse, the risk of its trauma during anal sex is quite high, which determines a higher risk of infection during such contacts. The risk of infection via kissing is extremely low, but it is possible if blood from the bleeding gums of an infected person gets onto minor wounds in the partner's oral mucosa.

The risk of perinatal infection without prophylaxis is 85–90% for HBeAg-positive mothers and 30% for HBeAg-negative mothers [23]. Intrauterine fetal infection is rare. As a rule, transmission occurs as a result of maternal blood entering the fetus's wounds when injured during passage through the birth canal [14]. Cesarean section reduces the risk of infection by more than a third [24]. Although HBsAg is detected in breast milk, breastfeeding is considered safe provided that dual prophylaxis of mother-to-child transmission is administered (see 3.10) [25].

In addition, the virus can be transmitted through the reuse of intravenous drug use equipment, medical procedures, household or cosmetic trauma to mucous membranes and skin [14]. According to the US Centers for Disease Control and Prevention, among HBV-infected individuals, 38% had multiple heterosexual partners, 11% had male-to-male anal sex, 15% used intravenous psychoactive substances, 12% had a history of surgery, 4% had percutaneous procedures (tattoos, piercings, etc.), 2% had prolonged household contact with an infected person, less than 1% had hemodialysis or blood transfusions, and about 1% were healthcare workers [26].

1.4 Features of Coding the Disease or Condition

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

The previously used code Z22.5 for hepatitis B virus carriers was excluded from the latest revision of ICD-10

1.5 Classification of the disease or condition

1.5.1 By phases of the infectious process:

Chronic HBeAg-positive infection (formerly immune tolerance phase)

Chronic HBeAg-positive hepatitis (formerly immune clearance phase)

Chronic HBeAg-negative infection (formerly immune control phase)

Chronic HBeAg-negative hepatitis (formerly reactivation phase)

HBsAg-negative phase (occult HBV infection)

1.5.2 By severity of clinical manifestations:

Clinical and laboratory reactivation in pre-cirrhotic stages

Exacerbation against the background of liver cirrhosis

1.5.3 By fibrosis stages:

0 – no fibrosis;

1 – mild fibrosis;

2 – moderate fibrosis;

3 – advanced fibrosis;

4 – liver cirrhosis.

1.5.4 By degree of inflammatory activity in liver tissue:

• minimal;

• mild;

• moderate;

• severe.

1.5.5 By presence of complications (at the stage of liver cirrhosis):

• uncomplicated;

• complicated.

Chronic HBV infection has 5 phases [1]. They are distinguished by the presence of an active inflammatory process in the liver (CHB if present, and HBV infection if absent) and signs of viral replication, which is determined by the presence of HBeAg in the blood.

The first phase is termed HBeAg-positive HBV infection. As the name implies, in this phase the virus replicates actively (viral load is very high and HBeAg is detected in the blood), but the macroorganism practically does not react to it, which is manifested by the absence of signs of hepatitis (normal blood ALT activity, absent or minimal necroinflammatory changes in the liver biopsy). In the previous classification, this phase was called "immune tolerance", meaning the absence of an immune system reaction to the virus, which entails its active replication in intact liver tissue, since the pathogen itself has no cytopathic effect. Patients have no signs of the disease, but are highly contagious due to the high concentration of the pathogen in biological fluids. This phase is particularly prolonged in individuals infected at birth and in children.

Over time, the immune system begins to react to the pathogen, damaging infected hepatocytes, which leads to the development of inflammation and fibrosis in the liver, increased blood ALT activity, and the appearance of other clinical and laboratory signs of hepatitis. However, the virus still continues to replicate actively, which is expressed by a fairly high viral load, albeit lower than in the first phase. This phase is HBeAg-positive CHB. Its outcome depends on the immune system's ability to bring viral replication under control. If it succeeds, inflammation in the liver resolves, but the pathogen continues to persist as cccDNA minichromosomes and integrated into the hepatocyte genome. This phase is termed HBeAg-negative HBV infection. It is characterized by a minimal or undetectable viral load, normal blood ALT activity, minimal or absent necroinflammatory changes in the liver biopsy, but varying degrees of fibrosis may be present as a result of active inflammation during the previous phase. Instead of HBeAg, anti-HBe antibodies are detected in the blood in this phase, i.e., HBeAg seroconversion occurs. Due to the absence of a pronounced pathological process in the liver, the risk of disease progression to liver cirrhosis (LC) and the development of hepatocellular carcinoma (HCC) in this phase is minimal. At the same time, in 1–3% of such patients per year, spontaneous clearance of HBsAg from the blood occurs with or without the appearance of anti-HBs antibodies (HBsAg seroconversion). In some cases, however, reactivation of the infection occurs with the re-development of CHB.

If the immune system is unable to completely suppress HBV replication, inflammation in the liver persists, but the viral load decreases and HBeAg seroconversion also occurs. This phase is termed HBeAg-negative CHB. Usually, these patients have mutations in the viral genome that reduce or abolish HBeAg expression, meaning that HBeAg-negativity in this case may be due not so much to the activity of the immune system, but rather to mutations in the virus itself.

In a small number of patients with chronic HBV infection, typically as an outcome of HBeAg-negative HBV infection, clearance of HBsAg from the blood is observed (the HBsAg-negative HBV infection phase) with or without anti-HBs appearance or HBs seroconversion. This phase corresponds to profound suppression, but not elimination, of the HBV infection; neither HBeAg nor HBV DNA is detected in the blood, but viral cccDNA can usually be detected in liver biopsy specimens. The inflammatory process in the liver is usually minimal, ALT is normal, but fibrosis that developed as a result of disease activity in earlier stages may persist. The prognosis in this case is determined by the stage of fibrosis. If cirrhosis has already developed, an increased risk of HCC persists; if not, the probability of disease progression to cirrhosis and HCC is minimal. However, immunosuppression may cause infection reactivation and the return of HBsAg [31, 73, 107-110, 113, 116, 126, 183].

Differential diagnosis of the phases of chronic HBV infection is presented in Table 1.

Table 1. Differential diagnosis of the phases of chronic HBV infection

Cirrhosis and HCC resulting from CHBV are categorized separately.

HDV (hepatitis D virus - hepatitis D virus) is capable of replicating only in the presence of HBV, therefore HDV co-infection and superinfection are considered as variants of HBV infection [89].

1.6 Clinical presentation of the disease or condition

In most patients, the disease is asymptomatic and is detected either during examination as part of preoperative or pre-admission preparation, or regarding dyspeptic symptoms usually not directly related to the presence of CHBV. Several years may elapse from the time of infection to diagnosis. Quite often, the disease manifests as asthenovegetative syndrome, which is expressed by weakness, severe fatigue, nervousness, and decreased performance. In some cases, the first manifestations of the disease are immunologically mediated extrahepatic conditions: arthritis and arthralgia, myositis, myocarditis, pericarditis, interstitial lung diseases, glomerulonephritis, tubulointerstitial nephritis, Sjögren's syndrome, polyarteritis nodosa and other vasculitis, anemia, pancytopenia, polyneuropathy, cryoglobulinemia. The appearance of jaundice facilitates diagnosis, which is an infrequent manifestation of the disease. In a fair number of patients, the diagnosis is established only after the manifestation of cirrhosis complications: bleeding from esophageal varices and the development of ascites [74].

On physical examination, in the absence of jaundice, pathological signs may be completely absent, or they may be limited only to mild hepatomegaly [19].

In untreated patients with CHBV, the 5-year risk of developing cirrhosis is 10–20%; in cirrhosis, the 5-year risk of decompensation is 20% [31, 32]; the annual risk of developing HCC in cirrhosis is 2–5% [27, 31]. It should be borne in mind that HCC can also develop in patients receiving effective therapy [28]. Risk factors for the development of HCC in HBV infection include: presence of cirrhosis, pronounced and prolonged inflammatory process in the liver, older age, male sex, genetic predisposition (family history of HCC), active smoking, combined liver damage (alcohol, other hepatotropic viruses, HIV infection, diabetes mellitus, etc.), high viral load and HBsAg content in the blood, virus genotype C, and its mutations [1, 28, 32, 138].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of the disease/condition:

The diagnosis of chronic HBV infection is established based on the detection of HBsAg in the patient's blood for at least 6 months of follow-up. The absence of HBV DNA in the presence of HBsAg does not exclude HBV infection.

Individuals with negative results for HBsAg, HBV DNA, and anti-HBs, but with a positive result for anti-HBc, are conventionally considered free of HBV infection and cured of it; however, persistence of the pathogen's cccDNA in hepatocytes is possible, which creates the probability of disease reactivation upon suppression of the immune system, including iatrogenic suppression.

Comments: This population includes:

• Pregnant women (in the 1st and 3rd trimesters of pregnancy);

• Recipients of blood and its components, organs, and tissues (if HBV infection is suspected and within 6 months after blood component transfusion);

• Staff of medical organizations (upon employment and thereafter once a year, additionally as clinically indicated);

• Patients of hemodialysis, kidney transplantation, cardiovascular and thoracic surgery, and hematology centers and departments (upon admission and as necessary based on clinical and epidemiological indications);

• Patients prior to scheduled surgical interventions and chemotherapy (no earlier than 30 days before admission or initiation of therapy);

• Patients with chronic diseases, including liver pathology (during the initial clinical and laboratory evaluation, additionally as indicated);

• Patients of narcological and dermatovenerological dispensaries, offices, and inpatient facilities, excluding patients with dermatomycosis and scabies (upon registration and thereafter at least once a year, additionally as indicated);

• Inmates and staff of round-the-clock childcare or adult residential care facilities (upon admission and thereafter at least once a year, additionally as indicated);

• Contacts of patients with acute and chronic hepatitis B foci (at least once a year; 6 months after isolation or recovery (death) of the patient with CHB);

• Individuals at risk for HBV infection (people who inject drugs and their sexual partners; sex workers and their partners; individuals with multiple casual sexual partners);

• Individuals in correctional facilities (upon admission to the facility, additionally as indicated);

• Donors of blood (and its components), organs, tissues, and semen (at each donation or retrieval of donor material);

• Children under 12 months of age born to HBV-infected mothers (at 2, 6 (if HBV DNA is not detected at 2 months), and 12 months of age);

• Immunocompromised patients (patients with cancer, patients on hemodialysis, patients receiving immunosuppressive therapy, etc.);

• Patients with liver disease of unknown etiology (during the initial clinical and laboratory evaluation).

• Blood testing for antibodies to the hepatitis B virus (Hepatitis B virus) core antigen (HBcAg) and antibodies to the hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) is recommended for all patients scheduled for any immunosuppressive therapy

[1] Methodological Guidelines MU 3.1.2792-10 "Epidemiological Surveillance of Hepatitis B", Moscow, 2011, p. 48.

[2] SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" VII. Prevention of viral hepatitis B and C (Registered with the Russian Ministry of Justice on February 15, 2021, No. 62500)

2.1 Complaints and Anamnesis

There are no symptoms specific to chronic HBV infection. The disease is usually asymptomatic or disguised as asthenovegetative syndrome and may manifest with complications of cirrhosis (ascites, esophageal variceal bleeding, hepatic encephalopathy) [74, 134].

2.2 Physical Examination

Physical examination may not reveal any abnormalities. Jaundice, hepatomegaly, and signs of cirrhosis (ascites, palmar erythema, abdominal wall venous collaterals, edema, splenomegaly) may be present [74, 134].

2.3 Laboratory Diagnostics

2.3.1. At the diagnostic stage:

Comments: performed to determine the patient's hemoglobin, erythrocyte, and platelet levels, as well as to detect general inflammatory responses.

Comments: uncomplicated viral hepatitis is typically characterized by changes in urine color, elevated urobilinogen, and bile pigments.

Comments: dysproteinemia is characteristic.

Comments: in the presence of hemorrhagic syndrome, a decrease in fibrinogen and clotting factors (II, V, VII, VIII, IX, X), a decrease in prothrombin time, prolonged blood clotting time, and a decrease in PTI are detected

Comments: HBV is a very common cause of hepatitis; therefore, when elevated ALT activity is detected, this infection should be ruled out as one of the first priorities. HBsAg is one of the earliest markers of HBV infection and is positive in all its phases except occult HBV infection, which lacks active liver disease. HBsAg usually appears in the blood 4–6 months after infection and prior to an increase in blood ALT activity. This test is inexpensive and widely available [21].

The phase of occult HBV infection, in which HBsAg is not detected in the blood, is characterized by the absence of an active process in the liver, which virtually rules out HBV infection as the cause of hepatitis [139, 140].

Comments: individuals at high risk for HDV infection include:

• patients with acute and chronic HBV infection;

• injection drug users and their sexual partners;

• commercial sex workers and their sexual partners;

• individuals with a high number of casual sexual partners;

• men who have sex with men;

• family members and individuals living in close contact with the patient;

• individuals who migrated from HDV-endemic regions;

• contacts in foci of acute and chronic hepatitis D;

• recipients of blood and its components, organs, and tissues;

• patients of hemodialysis centers and departments, kidney transplantation, cardiovascular and thoracic surgery, and hematology;

• medical staff;

• individuals in correctional facilities;

• immunocompromised patients (HIV infection, oncological diseases, undergoing hemodialysis, receiving immunosuppressants, etc.);

• children under 12 months of age born to mothers infected with HBV [68, 60, 70, 71].

• It is recommended that all patients with elevated blood ALT activity undergo testing for hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) in the blood to identify individuals infected with hepatitis B virus (Hepatitis B virus) [132, 133].

  Level of Recommendation C (Level of Evidence – 5)

• It is not recommended to perform primary molecular biological blood testing for hepatitis B virus (Hepatitis B virus) in all patients with elevated blood ALT activity for the early diagnosis of CHB, although HBV DNA appears in the blood 1–3 weeks earlier than HBsAg; however, testing for this marker is significantly more expensive, and when hepatitis develops, HBsAg is almost always present in the blood alongside HBV DNA [14, 134].

LoR CLE 5Level of Recommendation C (Level of Evidence – 5)

• If HBsAg is detected, it is recommended to perform a comprehensive laboratory blood test to determine the phase of the disease (quantitative PCR assay for hepatitis B virus (Hepatitis B virus) DNA in the blood, detection of antibodies to e-antigen (anti-HBe) of hepatitis B virus (Hepatitis B virus) in the blood, and qualitative detection of hepatitis B virus (Hepatitis B virus) e-antigen (HBeAg) in the blood) [1, 22, 119, 131, 133, 134].

  Level of Recommendation C (Level of Evidence – 5)

  Comments: Patient management tactics depend on the phase of the disease and the state of the liver [133].

• In patients with immunologically mediated extrahepatic diseases (arthritis or arthralgia of unclear etiology, myositis, myocarditis, pericarditis, interstitial lung disease, glomerulonephritis, tubulointerstitial nephritis, Sjögren's syndrome, polyarteritis nodosa, cutaneous vasculitis, anemia and pancytopenia of unclear etiology, polyneuropathy, cryoglobulinemia, etc.), it is recommended to consider qualitative testing for hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) in the blood, even with normal blood ALT activity, to confirm the etiological cause [132, 133].

  Level of recommendation C (evidence level – 5)

Comments: In some cases, HBV infection manifests with the aforementioned extrahepatic symptoms even in the absence of biochemical markers of liver damage [21].

• Given the common routes of transmission, all patients in whom HBsAg is detected are also recommended to undergo screening tests for class M and G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1 and HIV-2 in the blood; total class M and G antibodies (anti-HCV IgG and anti-HCV IgM) to hepatitis C virus (Hepatitis C virus) in the blood; class M antibodies (anti-HDV IgM) to hepatitis D virus (Hepatitis D virus) in the blood; and class G antibodies (anti-HDV IgG) to hepatitis D virus (Hepatitis D virus) in the blood to detect co-infection, as the concurrent course of infectious diseases worsens the prognosis and affects management tactics (see 3.7-3.9) [22, 88, 90, 131, 133, 134].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• When HBsAg is detected, it is also recommended to perform the detection of class G antibodies (anti-HAV IgG) to hepatitis A virus (Hepatitis A virus) in the blood to rule out past hepatitis A infection. If these antibodies are absent, hepatitis A vaccination should be performed, as co-infection worsens the prognosis [1, 22, 119, 131, 133, 134].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: the risk of developing HCC at the cirrhosis stage is approximately 1–5% per year. The probability of death within the first year after diagnosis in patients with HCC is 33% [74, 134].

2.3.2. During antiviral therapy (AVT):

Comments: neutropenia, anemia, and thrombocytopenia may develop. The complete blood count parameters are provided in Appendix A3.

Comments: performed to detect an increase in ALT activity, which makes it possible to assess the presence and activity of cytolysis syndromes. General routine biochemical blood test parameters are provided in Appendix A3

Comment: when conducting AVT using nucleotide and nucleoside reverse transcriptase inhibitors, this test must be performed at 6 months, 12 months, and then annually until the end of treatment.

The criterion for discontinuing or adjusting therapy due to its ineffectiveness is the absence of any decrease in blood HBsAg and a decrease in HBV viral load of less than 2log from baseline by week 12 of AVT.

Parameters are presented in Appendix A3.

2.3.4. During follow-up (dispensary observation):

     Comments: if necessary, the frequency of the test can be increased.

Comment: the risk of developing HCC at the cirrhosis stage is approximately 1–5% per year. The probability of death within the first year after diagnosis in patients with HCC is 33% [27, 28, 119].

2.4 Instrumental Diagnostics

• Patients with chronic HBV infection are recommended to undergo an abdominal ultrasound examination (comprehensive) for the timely diagnosis of HCC once a year; the frequency of ultrasound in liver cirrhosis is once every 3–6 months [27, 28, 29, 119, 34, 58, 59, 134].

GCP CLOE 4Grade of recommendation C (level of evidence – 4)

Comments: Liver cirrhosis and HCC in HBV infection can be asymptomatic and detected only by ultrasound. The presence of liver cirrhosis is an independent indication for initiating therapy. Despite the fact that the use of direct-acting antiviral drugs leads to a significant reduction in the risk of developing HCC, it still remains higher than the population average, which requires periodic screening to the extent determined by clinical guidelines for the prevention and treatment of HCC.

• CT and MRI of the liver during the initial evaluation of patients with HBV infection are not recommended, but can be performed if a focal lesion in the liver is detected on ultrasound to clarify its nature [28, 29, 119].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Liver ultrasound is able to detect signs of portal hypertension (ascites, portal vein dilation, splenomegaly). CT and MRI have no significant advantages over ultrasound in this regard, but are significantly more expensive. Liver ultrasound is also capable of detecting HCC in the majority of cases and is the main screening method for this disease. When lesions are detected in the liver, one should follow the available clinical guidelines for the diagnosis and treatment of liver lesions [29, 119].

Comments: The detection rate of liver tumors with a diameter of less than 1.0 cm, diagnostic accuracy, and differential diagnosis of HCC are increased when using MRI with a paramagnetic contrast agent, gadoxetic acid** [185–188, 214].

Comments: liver elastography must be performed on a validated device.

Comments: even with preserved liver function and no signs of portal hypertension on ultrasound, a morphological picture of liver cirrhosis may be present, which is an independent indication for initiating HBV therapy. In a number of patients, HBV infection may be combined with other diseases leading to the development of liver failure or portal hypertension. In this case, a non-invasive assessment of the severity of liver fibrosis should be performed for the differential diagnosis of these conditions from liver cirrhosis [1].

 Comments: esophagogastroduodenoscopy is performed to diagnose the grade of esophageal varices, as well as for variceal ligation in case of bleeding or for its prevention in patients with liver cirrhosis. If the patient's general condition is not severe, EGD is recommended to be performed on an outpatient basis using topical spray anesthesia. The procedure may be performed under sedation, which requires prior consultation and attendance by an anesthesiologist-resuscitologist.

• In patients taking TDF**, it is recommended to perform annual ultrasound densitometry or X-ray densitometry. These studies should also be performed if the administration of this drug is planned [1, 42, 56, 163].

GCP BLOE 2Grade of recommendation B (level of evidence – 2).

Comments: Unlike entecavir** and TAF**, the use of TDF** alone is associated with significant bone mineral density loss, which can lead to osteopenia and osteoporosis.

2.5 Other Procedures

Comments: liver biopsy is an invasive procedure with a significant risk of complications, and therefore it should be performed only if other diagnostic methods have yielded contradictory results and its data are necessary to determine management tactics [134, 161].

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

The primary goal of treatment is to improve the quality of life and prognosis of patients with HBV infection. The main surrogate goal is to reduce the viral load to an undetectable level. Elimination of HBsAg and HBeAg (if present) from the blood and normalization of blood ALT activity are also desirable.

It has been shown that a high level of viral replication, indicated by the viral load, is the strongest predictor of the development of liver cirrhosis and HCC in HBV infection, determining the prognosis [29-35].

HBeAg elimination with or without seroconversion is not an optimal biomarker of successful therapy, since HBeAg frequently reappears in the blood after its cessation [37].

HBsAg clearance («functional response» [36]) is an indicator of successful therapy, but it occurs rarely: in less than 10% of patients. Reappearance of HBsAg in the blood is extremely rare and typically indicates suppression of the immune system [38-39]. In patients who become HBsAg-negative, the risk of developing HCC is significantly reduced, but still remains at about 0.5% per year [40].

A decrease in viral load to an undetectable level is generally accompanied by the normalization of ALT activity in the blood, subsidence of necroinflammatory processes in the liver, and delayed progression of fibrosis [41]. If this does not occur, one should search for an additional factor leading to liver damage (alcohol, another hepatotropic virus, lipid metabolism disorders, etc.).

Unfortunately, under current conditions, achieving a complete cure for chronic HBV infection is practically impossible due to the integration of the virus into the hepatocyte genome and its persistence in the nucleus. Hypothetical elimination of cccDNA has been termed a «complete response», while the removal of the viral DNA integrated into the human genome is termed a «sterilizing response» [36].

3.1 Conservative Treatment

3.1.1 Indications for starting antiviral therapy (Algorithm 1)

• In chronic HBV infection, it is recommended to start antiviral therapy in the presence of:

1. CHB (viral load > 2000 IU/mL, elevated ALT activity in the blood, and/or a necroinflammatory histological activity index of the liver ≥ 6 according to Knodell or A2–3 according to METAVIR [Appendix G3]);

2. Cirrhosis at any detectable viral load, regardless of blood ALT activity [1, 133, 134].

   Level of recommendation C (evidence level – 5)

Comments: since cure of chronic HBV infection with current agents is practically impossible, the goal of treatment in CHB is to reduce the risk of developing cirrhosis and HCC. In patients with cirrhosis, the goal of treatment is to reduce the risk of disease decompensation [1].

1. in HBeAg-positive HBV infection (viral load > 2000 IU/mL, normal blood ALT activity > 30 IU/L for men and 19 IU/L for women, presence of HBeAg in the blood) in individuals over 30 years of age [133, 134];

2. in chronic HBV infection (normal blood ALT activity) with a family history of cirrhosis and HCC [134];

3. in chronic HBV infection (normal blood ALT activity) with suspected extrahepatic manifestations (polyarteritis nodosa and other vasculitis, glomerulonephritis, etc.).

4. in chronic HBV infection (normal blood ALT activity) with a viral load > 2000 IU/mL combined with fibrosis F2–3.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: in a number of cases, therapy for HBV infection can be prescribed even without signs of liver damage. For example, HBeAg-positive HBV infection in individuals over 30 years of age quite often leads to the development of HBeAg-positive CHB over time, and individuals with a family history of cirrhosis and HCC have an increased risk of developing cirrhosis and HCC even in the absence of evidence of an active pathological process in the liver. It is also reasonable to consider the use of antiviral therapy when extrahepatic manifestations of HBV infection are suspected, regardless of the severity of liver damage itself. Antiviral therapy may also be considered in patients without signs of active hepatitis, but with a significant viral load (> 2000 IU/mL) and significant liver fibrosis (F2–3) [1].

• It is not recommended to prescribe antiviral therapy to patients with HBV infection without signs of hepatitis, significant fibrosis (less than F2), and cirrhosis, except for the cases described above. Such patients are recommended to undergo dynamic monitoring for the timely detection of indications for initiating therapy (development of hepatitis and/or cirrhosis) [133, 134].

• The frequency of follow-up examinations depends on the phase of the disease and viral load (Appendix A3. Table: Examination of patients with HBV infection who are not indicated for therapy)

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: the risk of progression of HBV infection in patients without hepatitis and cirrhosis is extremely low, so prescribing antiviral therapy in these cases does not significantly affect the prognosis and is not recommended. However, over time, they may experience a resumption of the inflammatory process in the liver (increase in ALT activity in the blood) and gradual progression of fibrosis up to the development of cirrhosis, which is an indication for prescribing antiviral therapy. To detect such individuals in a timely manner, it is necessary to periodically determine ALT activity in the blood and perform non-invasive tests to assess liver fibrosis. The frequency of examination depends on the phase of the infection and viral load, i.e., the activity of virus replication, since the risk of infection reactivation is directly related to this. It is maximal with active virus replication (i.e., in HBeAg-positive patients) and minimal with insignificant replication (in HBeAg-negative patients with extremely low viral load) [107-109].

Comments: patients in whom HBsAg is no longer detectable in the blood have an extremely low risk of spontaneous reactivation of the infection, so treatment is not indicated for them. However, a decrease in immune system function, caused by either disease or iatrogenic factors, can lead to reactivation of the pathogen [72, 87, 214].

3 .1.2 Therapy with nucleotide and nucleoside reverse transcriptase inhibitors

• If there are indications for initiating therapy (see 3.1.1), it is recommended to use nucleotide and nucleoside reverse transcriptase inhibitors with a high genetic barrier to resistance:

  1) entecavir** (on an empty stomach: at least 2 hours after a meal or at least 2 hours before the next meal) at a dose of 0.5 mg once daily for most patients and 1 mg once daily for decompensated cirrhosis or in the presence of viral resistance to lamivudine** in patients with a history of prior therapy with this drug; patients who have not previously received nucleoside and nucleotide analogues with an eGFR of 30–49 ml/min receive the specified doses every 2 days, 10–29 ml/min every 3 days, less than 10 ml/min or on renal replacement therapy once a week [77, 121, 122, 123, 135, 148].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

or

2) Tenofovir** (TDF**): 300 mg once daily with food, swallowing the tablet whole without chewing, with water; for eGFR 30–49 ml/min, 300 mg every 2 days; for eGFR 10–29 ml/min or in individuals on renal replacement therapy, once a week after the dialysis procedure [50, 53, 43, 124, 179].

GCR C LEL 4 Grade of Recommendation C (Level of Evidence – 4)

or

3) Tenofovir alafenamide** (TAF**) 25 mg once daily with food, swallowing the tablet whole without chewing, with water; for eGFR greater than 15 ml/min, as well as in individuals on renal replacement therapy, dose adjustment is not required; contraindicated in individuals with eGFR less than 15 ml/min not receiving renal replacement therapy [41, 43, 50, 55, 199].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments:

Tenofovir alafenamide** and tenofovir** are preferred over entecavir** in patients with a history of prior therapy with nucleotide and nucleoside reverse transcriptase inhibitors.

Tenofovir alafenamide** and entecavir** are preferred over tenofovir** in the following categories of patients: age > 60 years; regular use of anabolic steroids or other drugs that may contribute to reduced bone mineral density; history of fractures; history of fragility bone fractures; osteoporosis; estimated glomerular filtration rate <60 ml/min/1.73 m²; albuminuria >30 mg/24 hours or moderate trace proteinuria; low phosphate level (<2.5 mg/dL); hemodialysis [45, 46, 49, 55, 54, 58, 165].

Entecavir** dose adjustment is required if the estimated glomerular filtration rate is <50 mL/min.

It is prescribed long-term, until HBsAg elimination, for at least 3 years (functional response).

Regardless of the appearance of anti-HBs, HBsAg elimination (functional response) should be considered the ideal treatment outcome for all antiviral therapy regimens. In this case, therapy with nucleotide and nucleoside reverse transcriptase inhibitors should be discontinued. Furthermore, discontinuation of nucleotide and nucleoside reverse transcriptase inhibitors is possible in patients with chronic hepatitis B (with detectable HBeAg) at pre-cirrhotic stages if HBeAg seroconversion occurs and HBV replication is absent for at least 12 months after HBeAg disappearance. The issue of discontinuing nucleotide and nucleoside reverse transcriptase inhibitors may also be considered for patients with chronic hepatitis B (with undetectable HBeAg) without liver cirrhosis, provided there is long-term (more than 3 years) suppression of HBV replication and adequate monitoring for HBV infection reactivation is ensured [98, 99].

In HBeAg-positive chronic hepatitis B, the use of entecavir** for 5 years leads to a partial functional response in 99% and HBeAg seroconversion in 53% of patients. When using TDF** in similar patients, a response was achieved in 97%, an HBeAg response in 49%, an HBsAg response in 10%, and a biochemical response in 73% of patients. With TAF** treatment for 2 years, a response was detected in 75% of patients, an HBeAg response in 22%, an HBsAg response in 1%, and a biochemical response in 75% [29, 41-43].

In HBeAg-negative chronic hepatitis B, the use of entecavir** for 5 years leads to a response in 98% and a biochemical response in 95%. For TDF** in similar patients over 3 and 8 years of therapy, the rates are as follows: response in 92–100% and 99%, biochemical response in 75% and 88%. An HBsAg response in the treatment of HBeAg-negative chronic hepatitis B with entecavir** and TDF** is achieved in <1% of cases, and even then only with prolonged administration (8 years or more). With TAF** administration for 2 years, a response develops in 90% of patients, and an HBsAg response in <1% [44-56].

Long-term administration of these drugs leads to a decrease in the severity of necroinflammatory liver processes, regression of liver fibrosis (including at the liver cirrhosis stage), improves the course and prognosis in decompensated liver cirrhosis, and reduces the need for liver transplantation and the risk of hepatocellular carcinoma [29, 52-56].

Comments: such patients are considered equivalent to those receiving long-term glucocorticoids and aged over 60 years.

• If osteopenia or osteoporosis develops during TDF** treatment, it is recommended to switch to entecavir** in the absence of lamivudine** resistance, or to TAF** if resistance is present [125].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: such cases include: patients with a GFR of less than 60 mL/min, uncontrolled arterial hypertension, proteinuria, uncontrolled diabetes mellitus, glomerulonephritis, hypophosphatemia, those taking nephrotoxic drugs, and organ transplant recipients.

Entecavir** and TAF** are drugs with a minimal risk of nephrotoxicity, and renal function monitoring during their administration is not required. Exceptions are patients at high risk for renal complications, for whom such monitoring is indicated primarily due to their comorbid condition. In contrast, TDF** has a higher nephrotoxic potential; therefore, monitoring of renal function (GFR and blood inorganic phosphorus testing) is indicated every 3 months during the first year of therapy and every 6 months thereafter for all patients taking TDF** and individuals at high risk for renal complications taking entecavir** and TAF** [42-43, 55-57, 80].

• It is recommended that patients with chronic hepatitis B receive long-term therapy with direct-acting antiviral drugs for many years until indications (stopping rules) for its discontinuation arise (Algorithm 2) [37, 60-63, 119, 160]:

  Level of recommendation validity B (evidence level – 2)

• Reactivation typically occurs within the first three months after stopping therapy; therefore, it is recommended to determine ALT activity and, if elevated, perform qualitative PCR testing for Hepatitis B virus DNA, quantitative PCR testing for Hepatitis B virus DNA, and, in HBeAg-positive patients at baseline, also test for Hepatitis B virus e antigen (HBeAg) in the blood monthly for the first three months of follow-up, then every three months in the first year, and every six months thereafter on a long-term basis for the early detection of infection reactivation. Given that approximately 20% of patients may achieve HBsAg seroconversion 2–3 years after discontinuing direct-acting antiviral therapy, annual testing for HBsAg is recommended during the follow-up period [127].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: treatment with direct-acting antiviral agents rarely leads to HBsAg clearance from the blood (less than 10% in HBeAg-positive infection and less than 1% in HBeAg-negative), however, HBsAg seroconversion is accompanied by an extremely low risk of infection reactivation after treatment discontinuation. HBeAg seroconversion occurs significantly more often (in approximately half of patients), but within the first 3 years after drug withdrawal, seroreversion (return of HBeAg to the blood) is observed in 10%, and in half of the patients the viral load becomes higher than 20,000 IU/mL (if it is lower, this is considered acceptable virological remission) [60]. In this regard, there is no consensus regarding the management strategy for patients with stable (more than 1 year) HBeAg seroconversion: some experts believe that therapy can be discontinued while closely monitoring patients, while others insist on continuing therapy until HBsAg clearance [1]. A similar problem occurs after discontinuing therapy upon achieving a long-term undetectable viral load in HBeAg-negative patients: within 3 years, it becomes higher than 2,000 IU/mL in half of the patients [37]. The return of viral activity in HBeAg-negative patients usually occurs within the first six months after discontinuation of direct-acting antiviral agents: the viral load increases first, followed with a lag of several months by an increase in HBsAg levels and ALT activity in the blood [61-63].

Comment: Generally accepted criteria for therapy discontinuation using NAs:

- Patients with HBeAg-positive chronic hepatitis B without liver cirrhosis who have achieved stable HBeAg seroconversion and undetectable HBV DNA, having received consolidation therapy for six months, or preferably a year.

- patients with HBeAg-negative chronic hepatitis B upon achieving HBsAg seroconversion and whose serum HBV DNA is undetectable in three blood tests taken at 6-month intervals

- in selected patients with HBeAg-negative chronic hepatitis B without liver cirrhosis who have achieved prolonged (~3 years) virological suppression under NA therapy, treatment discontinuation may be considered provided that strict monitoring is guaranteed with ALT and HBV DNA control for at least one year after treatment cessation [18, 62, 63, 83, 129, 192]

1. an increase in blood direct bilirubin is observed in two consecutive samples;

2. prothrombin time is prolonged by at least 2 seconds compared to values at the time of therapy discontinuation in two consecutive samples;

3. in two consecutive samples, ALT activity exceeds the upper limit of normal by 10 times or more;

4. ALT activity is 5-10 times higher than the upper limit of normal for at least 1 month;

5. ALT activity is 2-5 times higher than the upper limit of normal for at least 3 months;

6. ALT activity is 1.1-1.9 times higher than the upper limit of normal for at least 12 months without a decrease in blood HBsAg concentration;

7. viral load is greater than 2000 IU/mL for 12 months without a decrease in blood HBsAg concentration.

   In other cases, follow-up monitoring of blood ALT activity and quantitative determination of Hepatitis B virus DNA by PCR should be performed every 3 months [61-63, 127].

   Level of recommendation C (evidence level – 5)

   Comments: following the discontinuation of direct-acting antiviral drugs in HBeAg-negative patients, infection reactivation is quite frequently observed, which, as a rule, occurs during the first months. The return of viral activity can be favorable or unfavorable. In the first case, it is evidence of immune system activation and may lead to spontaneous HBsAg clearance—the most desirable achievable goal of HBV infection treatment. In the second case, it leads to active hepatitis without significant prospects for HBsAg elimination. Therefore, it is important to differentiate these cases, for which the aforementioned criteria were proposed. Unfavorable reactivation may be indicated by a decrease in liver function manifested as hyperbilirubinemia and/or hypocoagulation, an excessively active (ALT activity >10 times the upper limit of normal) or prolonged (>3 months with ALT activity 2-5 times the upper limit of normal, or >1 month with ALT activity 5-10 times the upper limit of normal) inflammatory liver reaction. In this case, re-administration of direct-acting antiviral drugs is required according to general rules, and therapy is continued until HBsAg is eliminated from the blood. If the inflammatory process is mild (blood ALT activity <10 times the upper limit of normal), is not accompanied by liver failure, and rapidly resolves spontaneously, treatment is not indicated, as there is no danger to the patient in this case, while there is an opportunity to achieve the optimal treatment goal—HBsAg elimination. Treatment should also be resumed if the inflammatory process is minimal (ALT = 1-2 times the upper limit of normal) but persists for a long time (>12 months), or if there is a significant viral load (>2000 IU/mL) for a prolonged period (>12 months) even without signs of hepatitis. Thus, cessation of therapy after prolonged viral suppression in HBeAg-negative patients leads to the following outcomes: functional response (HBsAg elimination in patients within the first 2-3 years) in 20%, partial functional response (undetectable viral load with persistent HBsAg in the blood) in 20-30%, need for long-term therapy in 40%, and intermediate cases (no viral suppression, but criteria for resuming therapy are not met) in 10-20% [61-63, 87, 192].

• In case of HBeAg seroreversion after discontinuation of direct-acting antiviral drugs, it is recommended to resume therapy. As a rule, the same drug that was used to achieve HBeAg seroconversion is utilized [61-63, 87].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

1. in case of non-response or virological breakthrough, it is recommended to substitute the drug according to Table Switch of drug in case of development of resistance to it in Appendix A3 [64].

2. in case of a partial response: when using drugs with a high barrier to resistance (entecavir**, TAF**, and TDF**), it is recommended to evaluate the dynamics of viral load reduction: if the dynamics are positive (viral load is progressively decreasing), the drug is kept; if a plateau is reached (insignificant changes in viral load), the drug is substituted according to Table Switch of drug in case of development of resistance to it in Appendix A3 [64].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: The use of modern systemic antiviral drugs in most cases leads to a virological response—an undetectable viral load using a highly sensitive method with a detection limit of 10 IU/mL at 12 months after the start of therapy. If this is not achieved, the most likely cause is insufficient patient adherence to therapy. If this is ruled out, the tactics depend on the dynamics of the viral load: if at 3 months from the start of therapy it has not decreased by 10-fold or more (non-response), the drug is substituted; if it decreases by more than 10-fold at 3 months, but does not reach an undetectable level at 12 months (partial response), then when using drugs with a low barrier to resistance, the development of resistance is assumed, which dictates drug substitution, whereas when using drugs with a high barrier to resistance, the viral load dynamics are studied. If it continues to decline steadily, it is believed that resistance has not developed, and the insufficient effect is associated with an excessively high viral load, so continuing therapy is recommended. If no decrease in viral load occurs, this indicates the development of resistance and requires drug substitution [64]. A relapse of viremia after achieving an undetectable viral load or an increase in viral load by more than 10-fold from its lowest level (virological breakthrough) is also a manifestation of viral resistance to the drug and requires its substitution [64, 79].

3.1.4 Pathogenetic therapy

Comments: baseline pathogenetic therapy includes a sparing regimen and diet. Fried, smoked, and pickled dishes, as well as hard fats (pork, mutton), are excluded from the diet. Alcohol in any form is strictly prohibited. Salt restriction to 5 g/day for patients with cirrhosis.

The organization of therapeutic medical nutrition for patients with chronic viral hepatitis B during inpatient treatment in medical organizations is carried out in accordance with the orders of the Russian Ministry of Health dated August 5, 2003, No. 330 "On measures to improve medical nutrition in healthcare institutions of the Russian Federation", dated June 21, 2013, No. 395n "On approval of medical nutrition standards", and dated September 23, 2020, No. 1008n "On approval of the procedure for providing patients with medical nutrition".

Comments: ademetionine**—the recommended dose is 5–12 mg/kg/day intravenously or intramuscularly. If maintenance therapy is necessary, it is recommended to continue taking the drug in tablet form at a dose of 800–1600 mg/day (2–4 tablets) for 2–4 weeks; ursodeoxycholic acid preparations**—daily dose of 10–15 mg/kg divided into 2–3 doses. Duration of treatment is 6–12 months or more) [111, 128]

Comments: administered intravenously as an infusion at a dose of 400 mL/day once daily for 10 days.

Comments: ornithine is administered intravenously as an infusion at a dose of 20 g previously diluted in 500 mL of infusion solution once daily for 10 days, and it is also prescribed orally at 1-2 packets (3-6 g of granules orally (after meals) pre-dissolved in 200 mL of water 2-3 times a day (daily dose 6, 9, 12, 18 g) and/or rifaximin is prescribed orally at 400 mg every 8 hours for 7 days or 550 mg twice daily for 6 months. Lactulose** is prescribed at an initial dose of 30-45 mL per day, then individually - orally until the target stool frequency of 4-5 times a day is achieved.

Comments: potassium-sparing diuretics (aldosterone antagonists): spironolactone** is prescribed at 100–400 mg/day (the dose is selected individually). If the effect of aldosterone antagonists is insufficient, the additional administration of sulfonamides is indicated—

– furosemide** at an initial dose of 20–40 mg/day or torasemide 5–20 mg/day.

Comments: infusion therapy: 800 – 1200 ml of 5% dextrose solution** intravenously drip, meglumine sodium succinate** at a rate of up to 90 drops/min (1–4.5 ml/min) — 400–800 ml/day. (Average daily dose: 10 ml/kg. Course of therapy: up to 11 days). Volume and duration depend on the patient's severity [208, 209]

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

In patients with CHB and liver cirrhosis developing bacterial complications (spontaneous bacterial peritonitis), treatment as well as primary and secondary prevention of their occurrence are carried out in accordance with the clinical guidelines for these respective complications.

3.2 Surgical Treatment

• In the presence of persistent signs of liver function decompensation, liver transplantation is recommended [1, 22, 105, 119, 132, 134, 166].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: additional examination is performed in accordance with the management protocol for patients on the waiting list at a transplant center.

• In the presence of esophageal varices, it is recommended to consider performing endoscopic variceal ligation of esophageal varices [1, 22, 119, 132, 134].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: esophageal variceal ligation is performed both for the prevention of bleeding and for its cessation.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, rehabilitation measures have not been developed.

5. Prevention and Dispensary Observation

5.1 Dispensary Follow-up

• After completion of antiviral therapy (AVT), dynamic monitoring by an infectious disease specialist at a medical organization at the place of residence or in a territorial specialized center is recommended. The frequency and scope of examination depend on the type of response achieved to the administered antiviral therapy and are described in section 2.3.4. Once a year for patients with CHB and once every 6 months for patients with liver cirrhosis [1, 22, 119, 132, 134].

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

5.2 Prevention

Prevention of hepatitis B should be carried out comprehensively regarding sources of the virus, transmission routes and factors, as well as the susceptible population, including risk groups ^[1],^[2] [1, 22, 119, 102, 134].

5.2.1 Specific Prevention

Comments: Standard hepatitis B vaccination schedule: 0-1-6 months. The first vaccination is given in the maternity hospital, the second upon reaching one month of age, and the third no earlier than 5 months later (at 6 months of life). The same schedule is used for vaccinating older children and adults (the second injection is given one month after the first, and the third 5 months later). The main principle is to adhere to the established interval between vaccinations.

Children from risk groups (mother has any clinical form of HBV infection, mother had acute hepatitis B in the third trimester of pregnancy, mother was not examined during pregnancy, there is a hepatitis patient in the family, child from a disadvantaged family) are vaccinated according to a different schedule: 0-1-2-12 months.

Comments. Induces seroconversion in high-risk patients and non-responders to conventional vaccines, as well as comorbid patients, including those with end-stage renal disease and immunocompromised individuals [189-191].

Comments: emergency prophylaxis is recommended for individuals with an increased risk of hepatitis B infection:

• for individuals not previously vaccinated against hepatitis B, or individuals whose vaccination is incomplete, or in cases where the level of Hbs antibodies is below the protective level (<10 IU/L), after accidental infections resulting from contact with infected material (during injections, dental procedures, blood transfusion, splashes of infected material into the mouth or eyes, etc.), human hepatitis B immunoglobulin . Depending on the nature of the contact, it is administered at a dose of at least 500 IU (10 ml) as early as possible after contact (if possible within 24-72 hours). Simultaneously (on the same day), hepatitis B vaccination should be started according to the 0-1-2-12 month schedule or the initiated course should be continued;

• for individuals belonging to high-risk groups for hepatitis B virus infection (patients in chronic hemodialysis centers, patients suffering from various diseases who receive frequent blood and blood product transfusions for vital indications, contacts in hepatitis B foci, etc.) who have not been vaccinated against hepatitis B, human hepatitis B immunoglobulin is administered before the start of the procedure - hemodialysis, blood transfusion and blood products, etc.; a single dose of 8-12 IU (0.16-0.24 ml/kg) is administered, maximum 500 IU (10 ml) every 2 months until seroconversion develops after vaccination. Simultaneously with the administration of human hepatitis B immunoglobulin, a course of hepatitis B vaccination should be started according to an accelerated schedule - 3 vaccine applications with an interval of 1 month. 12 months after the start of immunization, a 4th additional dose of vaccine for the prevention of viral hepatitis B** is administered. The first dose of the vaccine for the prevention of viral hepatitis B** is administered simultaneously with human hepatitis B immunoglobulin, but in different body sites [80-82].

• It is recommended for patients with CHB to be vaccinated against viral hepatitis A if they lack antibodies to HAV in their blood to prevent mixed infection [1, 22, 119, 132, 133, 134].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: this is carried out using vaccines for the prevention of viral hepatitis A**, which represent inactivated HAV virus adsorbed on aluminum hydroxide. Almost 100% of people develop protective levels of antibodies to the virus within one month after administration of a single vaccine dose. Even in the event of virus exposure, a single dose of the vaccine is able to protect the vaccinated person if applied within two weeks after contact with the virus. To form a long-lasting and stable immunity (20 years or more), manufacturers recommend administering two doses of the vaccine with an interval of 6 months to 6 years. As a rule, the vaccination schedule includes two intramuscular injections. Some manufacturers of vaccines for the prevention of viral hepatitis A** suggest considering the second vaccine administration not as an integral part of the vaccination schedule, but as a booster dose of the drug, which determines the long-term preservation of anti-HAV in the vaccinated person.

5.2.2 Non-specific prophylaxis

[1]Methodological Guidelines MU 3.1.2792–10 "Epidemiological Surveillance of Hepatitis B", Moscow, - 2011, - p. 48.

[2]SanPiN 3.3686–21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" VII. Prevention of viral hepatitis B and C (Registered with the Russian Ministry of Justice on 15.02.2021 N 62500)

[3]Methodological Guidelines MU 3.1.2792–10 "Epidemiological Surveillance of Hepatitis B", Moscow, - 2011, - p. 48.

[4]SanPiN 3.3686–21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" VII. Prevention of viral hepatitis B and C (Registered with the Russian Ministry of Justice on 15.02.2021 N 62500)

6. Organization of Medical Care

Patients with CHB must be followed up by an infectious disease specialist and a gastroenterologist.

Indications for emergency hospitalization [1, 22, 119, 132, 133, 134].

• bleeding;

• abdominal pain;

• onset of jaundice;

• headache with impaired consciousness;

• development of acute liver failure.

Indications for planned hospitalization [1, 22, 119, 132,133, 134].

• initiation of antiviral therapy for chronic hepatitis B (CHBV);

• adverse events resulting from CHBV antiviral therapy;

• prolonged persistent hyperthermia;

• exacerbation of chronic diseases;

• decrease in hematological parameters below acceptable limits;

• performance of a percutaneous liver biopsy (if necessary);

• severe extrahepatic manifestations of CHBV;

• decompensated / subcompensated liver cirrhosis resulting from CHBV.

Discharge from the hospital is performed based on clinical indications [1, 22, 119, 132, 133,134].

Type of care

Despite the planning of diagnostic and therapeutic measures for patients with chronic hepatitis B, care is of an urgent nature. Delaying the initiation of antiviral therapy or violating the schedule of treatment stages leads to a decrease in overall and relapse-free survival rates in these patients and worsens the prognosis for a particular patient.

Conditions for the provision of medical services

Diagnostic measures at the stage of diagnosis and during the period of antiviral therapy can be carried out in a specialized infectious disease hospital, on an outpatient basis, or in a day hospital setting. If significant adverse events develop, the patient is transferred (referred) for inpatient treatment.

7. Additional Information

Treatment of special patient populations

7.1 Antiviral therapy for patients with HBV infection reactivation

HBV infection reactivation is typically observed during the development of various immunodeficient states: post-transplant immunosuppression, prolonged therapy with glucocorticoids and tumor necrosis factor alpha (TNF-alpha) inhibitors, in patients with oncohematological and lymphoproliferative pathology, in HIV-infected individuals at any stage of the infection process upon the development of AIDS, as well as in patients with chronic mixed hepatitis B+C receiving direct-acting antiviral therapy for HCV infection.

HBV reactivation is more frequently observed in HBsAg-positive than in HBsAg-negative/anti-HBc-positive patients. However, prior to initiating immunosuppressive therapy, screening for anti-HBc is necessary for all patients, as HBV reactivation is possible in HBsAg-negative/anti-HBc-positive individuals. Such patients are also classified as a risk group for HBV reactivation. HBV reactivation is an absolute indication for the immediate prescription of nucleotide/nucleoside analogue (NA) inhibitors. Prior to initiating immunosuppressive therapy, all patients must be tested for antibodies to the surface antigen (HBsAg) in the blood and antibodies to the core antigen (HBcAg) of the hepatitis B virus (HBV) in the blood to rule out occult HBV infection. For patients from risk groups, it is advisable to administer prophylactic antiviral therapy before prescribing immunosuppressants and to continue it at least until the complete restoration of the immune system, under the control of HBV replicative activity and ALT levels.

Comments: it is recommended to prescribe direct-acting antiviral drugs with high antiviral activity and a high barrier to resistance: entecavir** (0.5 mg/day) for treatment-naive patients, and 1 mg/day for patients previously treated with lamivudine** or tenofovir** (300 mg/day). Individuals with positive anti-HBc must undergo qualitative determination of hepatitis B virus (HBV) DNA in the blood by PCR. If HBV DNA is detected in the blood serum, a course of antiviral therapy using direct-acting antiviral drugs with high antiviral activity and a high barrier to resistance should be initiated. When HBV DNA is at an undetectable level, regardless of anti-HBs status, all patients receiving chemo- and/or immunosuppressive therapy must be closely monitored. Thus, during the first month of chemo- or immunosuppressive therapy, blood ALT activity is determined weekly, then once a month. Quantitative determination of hepatitis B virus (HBV) DNA in the blood by PCR is performed at 4 and 12 weeks from the start of treatment, and then every 3 months of antiviral therapy [30, 67, 119].

7.2 Etiotropic therapy and prevention of chronic hepatitis B in the post-transplantation period.

Effective prevention of HBV infection after orthotopic liver transplantation (OLT) is determined by a sufficient and effective protective level of anti-HBs (at least 500 IU/L shortly after OLT and at least 100 IU/L in the long term). The presence of anti-HBs can be ensured in two ways: by the administration of human hepatitis B immunoglobulin (HBIG) or active immunization (vaccination).

Another opportunity to prevent acute graft infection associated with HBV replication after OLT is the administration of direct-acting antiviral drugs.

Comments: to minimize the risk of recurrent HBV infection after OLT, it is necessary to ensure an anti-HBs level of more than 500 IU/L during the 1st week, more than 250 IU/L from weeks 2 to 12, and to maintain a level of more than 100 IU/L thereafter. Currently, the administration of high doses of intravenous human hepatitis B immunoglobulin (HBIG) in combination with direct-acting antiviral drugs is used. HBIG administration is started intravenously during the anhepatic phase of the operation at a dose of 10,000 IU, continued daily during the first week at 2,000 IU, and then every 2 weeks for 6–12 months (or more) after OLT at doses of 500–2,000 IU. The dose of HBIG during these periods should be determined individually, under the control of blood anti-HBs levels. Discontinuation of HBIG is possible after 2 years of use, followed by monotherapy with direct-acting antiviral drugs.

7.3 Antiviral therapy for patients with CHBV at the stage of decompensated liver cirrhosis

• All patients with HBV-associated decompensated LC are recommended to immediately start antiviral therapy (adjusted for GFR as described above for renal failure and taking into account overweight due to excess fluid in ascites): entecavir** 1 mg daily for life or TAF** 25 mg daily for life [1, 75-77, 130, 131].

Entecavir** Grade of recommendation B (level of evidence – 2).

TAF** Grade of recommendation C (level of evidence – 5).

7.4 Antiviral therapy for patients with HIV/CHBV coinfection

Comments: Discontinuation of tenofovir** in these patients is highly undesirable due to the high risk of HBV infection reactivation. At the same time, it should be remembered that immune reconstitution during effective antiretroviral therapy can lead to LC decompensation due to the activation of the immune response against HBV, which requires careful monitoring of patients with LC and a low blood CD4⁺ cell count [84-86].

7.5 Antiviral therapy for patients with CHCV/CHBV coinfection

7.6 Antiviral therapy for patients with CHBV/CHHD coinfection

Treatment according to clinical guidelines: Chronic viral hepatitis D (CHVD) in adults

7.7 Antiviral therapy for pregnant patients with CHBV

Comments: if the maternal viral load is less than 20,000 IU/mL, the risk of perinatal infection in an infant who has received standard preventive measures (human hepatitis B immunoglobulin administered simultaneously with the hepatitis B vaccine**) does not exceed 1%. At a viral load of 200,000 IU/mL, it is 2.6%; at 2,000,000 IU/mL, it is 6.6%; and starting from 20,000,000 IU/mL, it is more than 15%. The use of tenofovir** in mothers with a viral load greater than 10,000,000 IU/mL reduced the risk of neonatal infection from 20% to 2% (all newborns received standard dual prophylaxis). Thus, in mothers with a low viral load, the risk of perinatal transmission of the pathogen during dual prophylaxis is quite small, so prophylactic treatment of the mother is not indicated. However, with a high viral load, the risk remains very high despite dual prophylaxis; therefore, such patients should be prescribed tenofovir** [97–104]. It is not recommended to discontinue the drugs after delivery due to the possible development of a CHBV flare, which is usually not severe and resolves spontaneously, but remains undesirable [23, 172, 110576, 177, 179].

Comments: Data on the secretion of tenofovir** into breast milk and its effect on neonatal development are limited; therefore, product labeling does not recommend breastfeeding during postpartum chemotherapy. Nevertheless, women taking tenofovir** should be provided with information about the lack of precise safety data on the drug during breastfeeding and the benefits of breastfeeding so that the patient can make an informed choice [174]. This recommendation is based on data showing that in HIV-infected women receiving tenofovir**, the secretion of the drug metabolite into milk is negligible, amounting to 0.03% of the recommended daily pediatric dose of the drug [175].

7.7 Antiviral therapy for healthcare workers with CHBV

• Due to the fact that there is no regulatory act in the Russian Federation prohibiting medical workers diagnosed with "hepatitis B or C" from practicing their profession (work clearance is decided by a medical commission at a specialized infectious diseases medical institution on a case-by-case basis) [1, [2], healthcare workers with CHBV who perform invasive medical procedures involving contact with patients' biological fluids are recommended to be prescribed antiviral therapy with nucleoside and nucleotide reverse transcriptase inhibitors when HBV DNA replication levels exceed 200 IU/mL in order to reduce the risk of nosocomial infection [156, 157, 158].

  Grade of recommendations C (Level of evidence – 5).

7.8 Antiviral therapy for patients with CHBV and CKD on dialysis or post-kidney transplantation

7.9 Antiviral therapy for patients with CHBV and extrahepatic manifestations

Comments: in the presence of glomerulonephritis, vasculitis, arthritis/arthralgia, or peripheral polyneuropathy, patients should be tested for antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) in the blood, as these conditions may be the first and only manifestations of HBV infection. The use of interferons in these conditions in some cases worsens the course of the immune-mediated disease and is therefore not recommended. Unfortunately, there are currently no clear guidelines on immunosuppressive therapy for immune-mediated complications of HBV infection, but the use of immunosuppressants and glucocorticoids in combination with direct-acting antivirals is not contraindicated [117–119].

Factors that increase the risk of liver failure and death [1, 22, 119, 132, 133, 134, 135]:

• liver cirrhosis;

• mixed infection with hepatotropic viruses and human immunodeficiency virus;

• somatic pathology – 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

Factors negatively affecting the outcome of antiviral therapy [1, 22, 119, 132, 133, 134, 135]:

1. Patient non-adherence to direct-acting antiviral therapy;

2. Occurrence of adverse events requiring medical management or discontinuation of antiviral therapy.

[1] Part 4 of Article 213 of the Labor Code of the Russian Federation State expert review of working conditions

[2] Appendix No. 2 to Order of the Russian Ministry of Health No. 29n dated February 28, 2021

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Abdurakhmanov D.T. – Doctor of Medical Sciences, Professor, Department of Internal, Occupational Diseases and Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

2. Batskikh S.N. – Doctor of Medical Sciences, Leading Researcher, Center for Diagnostics and Treatment of Liver Diseases, A.S. Loginov Moscow Clinical Scientific Center, Department of Healthcare of Moscow

3. Zharkova M.S. – Candidate of Medical Sciences, Head of the Hepatology Department, V.H. Vasilenko Clinic of Propedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

4. Zhdanov K.V., Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Honored Scientist of the Russian Federation, Director of the D.I. Ivanovsky Research Institute of Influenza (St. Petersburg Research Institute of Epidemiology and Microbiology / Research Center of the Federal Medical-Biological Agency), Chief Freelance Specialist in Infectious Diseases of the Health Committee of St. Petersburg.

5. Ivashkin V.T. – Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, President of the Russian Gastroenterological Association and the Russian Society for the Study of the Liver, Head of the Department of Propedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Honored Doctor of the Russian Federation, Honored Scientist of the Russian Federation, Laureate of the Russian Government Prize in Science and Technology (2007) and Education (2013).

6. Kozlov K.V., Doctor of Medical Sciences, Professor of the Department of Infectious Diseases (with a course of medical parasitology and tropical diseases), S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation;

7. Maslennikov R.V. – Candidate of Medical Sciences, Assistant Professor, Department of Propedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

8. Novak K.E. – Candidate of Medical Sciences, Associate Professor, Department of Infectious Diseases in Adults and Epidemiology, St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation

9. Priyma E.N. – Candidate of Medical Sciences, Assistant Professor, Department of Infectious Diseases in Adults and Epidemiology, St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation

10. Sagalova O.I. – Doctor of Medical Sciences, Professor, Department of Infectious Diseases, South-Ural State Medical University of the Ministry of Health of the Russian Federation, Head of the Infectious Diseases Department of the Clinic of SUSMU of the Ministry of Health of Russia

11. Sukachev V.S. – Candidate of Medical Sciences, Senior Lecturer, Department of Infectious Diseases (with a course of medical parasitology and tropical diseases), S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation;

12. Syutkin V.E., Doctor of Medical Sciences, Professor, Department of Surgery with courses of oncosurgery, endoscopy, surgical pathology, clinical transplantology and organ donation, Institute of Professional Education, A.I. Burnazyan Federal Medical Biophysical Center of FMBA of Russia; Leading Researcher, Liver Transplantation Department, Sklifosovsky Research Institute for Emergency Medicine, Department of Healthcare of Moscow

13. Tikhonov I.N. – Member of the Russian Society for the Study of the Liver, Assistant Professor, Department of Propedeutics of Internal Diseases, Gastroenterology and Hepatology, Gastroenterologist at the Hepatology Department of the V.H. Vasilenko Clinic of Propedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

14. Chulanov V.P. – Doctor of Medical Sciences, Professor, Deputy Director for Science and Innovative Development, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health, Professor, Department of Infectious Diseases, I.M. Sechenov First Moscow State Medical University, Chief Freelance Infectious Disease Specialist of the Russian Ministry of Health;

15. Sheptulin A.A. – Doctor of Medical Sciences, Professor, Department of Propedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health

16. Shirokova E.N. – Doctor of Medical Sciences, Professor, Department of Propedeutics of Internal Diseases, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Head of the Innovative Therapy Research Department, Research Center of I.M. Sechenov First Moscow State Medical University

17. Esaulenko E.V., Doctor of Medical Sciences, Professor, Head of the Department of Infectious Diseases in Adults and Epidemiology, St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation;

All members of the working group are members of the Academician V.I. Pokrovsky National Association of Infectious Disease Specialists or members of the Russian Society for the Study of the Liver.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

The proposed guidelines aim to provide practitioners with modern concepts of the etiology and pathogenesis of HBV infection and to introduce currently used algorithms for its diagnosis and treatment.

1. Infectious disease specialist;

2. General practitioner (internist);

3. Gastroenterologist;

4. General practitioner (family physician);

5. Medical students, residents, PhD students (postgraduate fellows).

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. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of evidence certainty indicating the used

classification of levels of evidence certainty (LEC)

Table 3. Levels of clinical evidence (LCE) indicating the classification system used

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 on 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, "On Immunoprophylaxis of Infectious Diseases"

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

3. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

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

5. Order of the Ministry of Health and Social Development of Russia No. 1664n dated December 27, 2011, "On Approval of the Nomenclature of Medical Services."

6. Order of the Ministry of Health and Social Development of Russia No. 69n of January 31, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases".

7. Order of the Ministry of Health of Russia No. 1183n dated December 20, 2012, "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers"

8. Order of the Ministry of Health of Russia No. 700n of October 7, 2015, "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education".

9. Order of the Ministry of Health of Russia No. 1024n dated December 17, 2015, "On Classification and Criteria Used in Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise."

10. 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."

11. Methodological Guidelines "MU 3.1.2792-10. 3.1. Prevention of Infectious Diseases. Epidemiological Surveillance of Hepatitis B (approved by the Chief State Sanitary Doctor of the RF on December 20, 2010).

12. Sanitary Rules and Norms SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" (approved by the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021).

13. Order of the Ministry of Health of Russia No. 786n dated November 9, 2012, "On Approval of the Standard of Specialized Medical Care for Chronic Viral Hepatitis B"

14. "Labor Code of the Russian Federation" No. 197-FZ dated December 30, 2001 (ed. February 14, 2024), Article 213. State Expertise of Working Conditions.

15. Order of the Ministry of Health of Russia No. 29n dated January 28, 2021 (ed. February 1, 2022), "On Approval of the Procedure for Conducting Mandatory Preliminary and Periodic Medical Examinations of Employees Provided for in Part Four of Article 213 of the Labor Code of the Russian Federation, the List of Medical Contraindications to Performing Work with Harmful and (or) Hazardous Production Factors, as well as Work Requiring Mandatory Preliminary and Periodic Medical Examinations"

16. Order of the Ministry of Health of the Russian Federation No. 330 dated August 5, 2003, "On Measures to Improve Therapeutic Nutrition in Healthcare Institutions of the Russian Federation."

17. Order of the Ministry of Health of the Russian Federation No. 395p dated June 21, 2013, "On Approval of Therapeutic Nutrition Norms."

18. 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."

    Examination of patients with HBV infection who do not require therapy

* in the absence of negative dynamics for 3 years, it is possible to switch to a monitoring regimen similar to that for individuals with a viral load <2000 IU/mL.

** 4 times in the first year and 2 times in subsequent years.

*** Less frequently if the HBsAg level is less than 1000 IU/mL, and more frequently if it is above this figure [1].

Switching the drug upon the development of resistance to it

Toxicity criteria

To assess immediate complications of antiviral therapy in our clinical guidelines, we were guided by the toxicity criteria proposed by the International Society of Paediatric Oncology (SIOP) and presented in Table App.3.

Table – Toxicity criteria

*N - normal laboratory value adopted by the healthcare institution

Monitoring schedule for laboratory parameters during antiviral therapy (AVT) using nucleos(t)ide analogues

* in case of a positive qualitative test

** in case of completion of AVT Determination of Hepatitis B virus DNA in blood by PCR, qualitative test (Determination of Hepatitis B virus DNA in blood by PCR, quantitative test) and  Determination of Hepatitis B virus surface antigen (HBsAg) in blood qualitatively (quantitatively) is performed at 3 and 6 months.

Appendix B. Physician Action Algorithms

Algorithm 1. Algorithm for patient selection for chronic HBV infection therapy

Algorithm 2. Conditions for cessation of direct-acting antiviral therapy (stopping rules)

Algorithm 3. Management in case of therapy failure

Algorithm 4. Conditions for discontinuing interferon therapy (stopping rules)

Appendix C. Patient Information

Dear patient! You are infected with the hepatitis B virus (HBV). Unfortunately, even modern treatments cannot completely cure it, but they can bring the disease under control, which reduces the risk of developing cirrhosis and liver cancer. Not all cases of the disease require treatment. In some cases, the disease has extremely low activity and should only be monitored. The necessity and scope of therapy will be determined by your attending physician. They will also prescribe the list of required tests and their frequency. You should not independently discontinue or replace medications, even if you feel better and consider yourself healthy. The disease can be asymptomatic for a long time. For any emerging questions, please contact your attending physician.

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

Appendix G1. Assessment of the severity of liver cirrhosis using the Child-Pugh score

Name: Child-Pugh score for assessing the severity of liver cirrhosis

(Child-Pugh classification)

Source (official developer website, validation publication):

Child CG, Turcotte JG (1964). "Surgery and portal hypertension". In Child CG (ed.). The liver

and portal hypertension. Philadelphia: Saunders. pp. 50–64

Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973). "Transection of the

oesophagus for bleeding oesophageal varices". The British Journal of Surgery. 60 (8): 646–9.

doi:10.1002/bjs.1800600817. PMID 4541913

Type: rating scale

Purpose: scale for assessing the severity of liver cirrhosis

Content:

Points are assigned from 1 to 3 based on the value of each parameter and then summed up.

Key:

class A (Child A): 5–6 points

class B (Child B): 7–9 points

class C (Child C): 10–15 points

Assessment of survival in patients with liver cirrhosis based on the Child-Pugh classification

There are various survival estimates for patients with liver cirrhosis, including the following:

Appendix G2. Stages of liver fibrosis according to the METAVIR scale

Name: METAVIR scale

Source: Shiha G., Zalata K. Ishak versus METAVIR: terminology, convertibility and

correlation with laboratory changes in chronic hepatitis C. Liver biopsy. 2011, 10, 155-170.

Type: Scale

Content and key (interpretation):

Appendix G3. Stages of liver fibrosis according to the Knodell scale

Name: Stages of liver fibrosis according to the Knodell scale

Source: E M Brunt. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology. 2000 Jan;31(1):241-6. doi: 10.1002/hep.510310136.

Type: scale

Content and key (interpretation):

 Fibrosis is graded on a scale from 0 to 4:

• 0 points — no fibrosis;

• 1 point — fibrosis and expansion of portal tracts — mild fibrosis;

• 3 points — porto-portal and/or porto-central septa — severe fibrosis (precirrhosis);

• 4 points — cirrhosis.

Appendix G4. Calculation of the FIB-4 fibrosis index

Name: 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 and scoring scale for the fibrosis index

Calculation formula: FIB−4=Age (years)*AST/platelets ( 9 10 /L) * √ALT Age - patient's age (years)

AST - patient's aspartate aminotransferase value

Platelets (9 10 /L) - patient's platelet count in 1 L of blood √ALT - square root of the patient's ALT value

Key (interpretation):

Appendix G5. 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, 13 (6), e0199760.

Type: Index

Content: 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 G6. Calculation of the FibroMax fibrosis index

Name: FibroMax fibrosis index

Source: Morra R, Munteanu M, Imbert-Bismut F. et al. FibroMAX: towards a new universal biomarker of liver disease? 2007.- Review. Sep;7(5):481-90. doi: 10.1586/14737159.7.5.481.

Halfon P, Munteanu M, Poynard T. FibroTest-ActiTest as a non-invasive marker of liver fibrosis. Gastroenterol Clin Biol. 2008 Sep;32(6 Suppl 1):22-39. doi: 10.1016/S0399-8320(08)73991–5

Type: laboratory and calculation method

Content: a comprehensive non-invasive method for assessing liver fibrosis, steatosis, and inflammatory changes. The test consists of 2 calculation algorithms and is performed based on the mathematical processing of six biochemical blood parameters: Alpha-2-macroglobulin, Apolipoprotein A1, Alanine aminotransferase, Bilirubin

Gamma-glutamyltransferase, Haptoglobin. The FibroMax result also includes values for FibroTest, SteatoTest, and, if relevant risk factors are present, ActiTest (for viral hepatitis C and B), NashTest (for obesity, diabetes mellitus), and AshTest (for alcohol abuse).

Key (interpretation): All test results range from zero to one. The indicator depends on disease severity (activity level). Results are converted into the METAVIR system:

Appendix G7. Minimally invasive method for the diagnosis of liver fibrosis: FibroTest

Name: FibroTest method

Source: Salkic NN, Jovanovic P, Hauser G, Brcic M. FibroTest/Fibrosure for significant liver fibrosis and cirrhosis in chronic hepatitis B: a meta-analysis. J Gastroenterol. 2014 Jun;109(6):796-809. doi: 10.1038/ajg.2014.21. Epub 2014 Feb 18.

Type: laboratory and calculation method

Content: a minimally invasive method for diagnosing liver fibrosis (a pathology in which normal organ tissue is replaced by scar tissue). Venous blood is used as the test material. The FibroTest consists of 2 calculation algorithms and is performed based on the mathematical processing of six biochemical blood parameters: alpha-2 macroglobulin, haptoglobin, apolipoprotein A1, GGT (gamma-glutamyltransferase), total bilirubin, and ALT (alanine aminotransferase). The mathematical processing results obtained during the analysis allow for the assessment of the degree of pathological changes in the liver.

Key (interpretation):

Result evaluation is performed according to the severity of the disease on a scale from 0 to 4 and is designated by the letter F.