List of Abbreviations
ALT – alanine aminotransferase
AST – aspartate aminotransferase
AFP – alpha-fetoprotein
BR – biochemical response
HBV – hepatitis B virus
HDV – hepatitis D virus
HIV – human immunodeficiency virus
VR – virological response
GGT – gamma-glutamyl transferase
HCC – hepatocellular carcinoma
HBV DNA – hepatitis B virus deoxyribonucleic acid
VLEL – vital and essential drugs
INR – international normalized ratio
sVR – sustained virological response
PCR – polymerase chain reaction
HDV RNA – hepatitis D virus ribonucleic acid
TPO – thyroid peroxidase
US – ultrasound examination
CHBV – chronic viral hepatitis B
CHDV – chronic viral hepatitis D
LC – liver cirrhosis
pVR – partial virological response
ALP – alkaline phosphatase
LCE – level of confidence of evidence
GRS – grade of recommendation strength
anti-HDV – antibodies to hepatitis D virus
APRI – AST-to-Platelet Ratio Index
FIB-4 – Fibrosis-4 index
HBsAg – hepatitis B virus surface antigen
HBeAg – hepatitis B virus e-antigen
Terms and Definitions
Clinical guidelines (management protocol) – a normative document of the healthcare standardization system that defines the requirements for providing medical care to a patient with a specific disease, syndrome, or clinical situation.
Quality of medical care – a set of characteristics reflecting the timeliness of medical care, the correctness of the choice of prevention, diagnosis, treatment, and rehabilitation methods in providing medical care, and the degree of achievement of the planned result.
Virological response (VR) – a decrease in HDV RNA levels by 2 or more log10 compared to baseline during treatment, indicating the time point of response assessment in weeks (e.g., 48 weeks from the start of treatment – VR-48).
Complete virological response (cVR) – a decrease in HDV RNA levels to undetectable (aviremia) during treatment, indicating the time point of response assessment in weeks (e.g., 48 weeks from the start of treatment – cVR-48) and after treatment completion.
Partial virological response (pVR) – a decrease in HDV RNA levels by 1 log10 or more, but less than 2 log10, compared to baseline, indicating the time point of response assessment in weeks (e.g., 48 weeks from the start of treatment – pVR-48).
Biochemical response (BR) – a decrease or normalization of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity compared to baseline, indicating the time point of response assessment in weeks (e.g., 48 weeks from the start of treatment – BR-48) and after treatment completion.
Combined virological and biochemical response – a decrease in HDV RNA levels by 2 or more log10 compared to baseline or to undetectable (if baseline level <100 IU/mL) and normalization of alanine aminotransferase (ALT) activity in the blood.
Histological response – absence of progression or a decrease in the degree of necrosis, inflammation, or fibrosis upon repeat morphological examination of liver biopsy tissue compared to baseline.
Serological response – a decrease in the level and disappearance of hepatitis B virus surface antigen (HBsAg) in the blood, and the formation of antibodies to HBsAg (HBsAg seroconversion) during or after treatment completion.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Chronic viral hepatitis D (CHDV) – a chronic inflammatory liver disease caused by the hepatitis D virus in individuals with the hepatitis B virus surface antigen in their blood (HBsAg-positive individuals) lasting for more than 6 months, accompanied by a high risk of developing liver cirrhosis (LC), hepatic complications (decompensation, hepatocellular carcinoma (HCC), death, liver transplantation) [1-8].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Hepatitis D virus (HDV) – an RNA-containing virus of the genus Deltavirus (deltaviruses), a defective satellite virus of the hepatitis B virus (HBV) that lacks its own envelope and utilizes HBsAg (HBV surface antigen) to build it.
The HDV genome consists of a single-stranded circular RNA (the smallest among all human RNA-containing viruses), to which the delta antigen (HDAg) is bound. The virus lacks its own enzyme systems and utilizes human polymerases for replication.
HDV lacks its own enzyme systems (polymerases), which explains the impossibility of developing direct-acting antiviral drugs. The virus utilizes human DNA-dependent RNA polymerases for replication in hepatocytes, while being capable of suppressing HBV DNA polymerase activity and HBV replication.
The entry of HDV into the cell is accomplished by the attachment of the L-HBsAg viral envelope (pre-S1 domain bound to myristic acid) to NTCP (sodium taurocholate co-transporting polypeptide), the entry receptor for HDV and HBV on the basolateral membrane of the hepatocyte, which functions as a bile acid transporter [9-12]. Another mechanism of HDV spread in the liver is the infection of dividing hepatocytes owing to the small size of its genome [13].
There are 8 genotypes of HDV, of which genotype 1 is the most common, predominating in Europe and North America; genotype 2 prevails in Asia, the Middle East, and Egypt; genotype 3 (the most pathogenic) is found in South America, particularly in the Amazon basin; genotype 4 in Japan, China, and Taiwan; genotypes 5–8 in Africa, and due to migration, have been detected in European countries in recent years [14–16].
In Russia, genotype 1 is predominant and is associated with a severe disease course, progression to liver cirrhosis (LC), and the development of hepatocellular carcinoma (HCC); genotype 2 is detected in the Republic of Sakha (Yakutia) (45% of cases) [17].
1.3 Epidemiology of the Disease or Condition
The transmission routes of HDV are similar to those of HBV: parenteral (blood transfusion, surgical interventions, injection drug use), sexual, and from an infected mother to child during childbirth. In endemic areas for chronic hepatitis D (CHD), infection of patients' relatives and the formation of familial clusters of chronic infection, as well as the spread of HDV among family members through close household contact, are characteristic.
HDV is resistant to high temperatures, acids, and ultraviolet radiation, but is inactivated by alkalis and proteases; repeated freezing and thawing do not affect its activity.
The exact global prevalence of HDV infection remains unclear due to differences in the sensitivity and specificity of the tests used, the lack of standardization of test systems in accordance with WHO recommendations, and the low frequency of testing for HDV markers in HBV patients due to the unavailability of tests or a lack of specialist awareness and vigilance; there are significant variations in infection prevalence within individual countries, and the zones of maximum HDV prevalence do not coincide with those of HBV. The detection rate of antibodies to hepatitis D virus in the blood among HBsAg-positive patients worldwide ranges from 4 to 15%, which corresponds to 15–72 million infected individuals [14–16].
The exact prevalence of CHD in the Russian Federation is unknown, as patients with HDV infection were not subject to mandatory registration. Based on prevalence rates in the European part of the Russian Federation from individual studies (5% among HBsAg-positive individuals), the estimated number of HDV-infected people in Russia may reach 125,000. There are endemic zones with a high prevalence of HDV among HBsAg-positive individuals: the Republic of Tyva (up to 47%), the Republic of Sakha (Yakutia) (up to 35%), and the Republic of Dagestan (up to 15%) [17].
The prevalence of HDV remains stable despite vaccination against hepatitis B, driven by population migration from endemic to non-endemic areas, drug use (38% among HBsAg-positive injection drug users), risky sexual behavior (17% among HBsAg-positive individuals with risky sexual behavior), and ongoing intrafamilial transmission in endemic foci [14–16].
The disease is diagnosed at the stage of liver cirrhosis in 27–82% of patients (in clinical trials) due to the lack of early universal testing for HDV markers in individuals with HBV [18].
1.4 Features of Coding the Disease or Condition
B18.0 – Chronic viral hepatitis B with delta-agent
1.5 Classification of the disease or condition
0 – no fibrosis;
1 – mild fibrosis;
2 – moderate fibrosis;
3 – advanced fibrosis;
4 – cirrhosis.
1.6 Clinical presentation of the disease or condition
HDV causes hepatitis in the form of coinfection (simultaneous infection with HBV and HDV with recovery in 90% of patients within 6 months) and superinfection (when HDV is added to pre-existing HBV infection, followed by chronicity in 70–90% of patients); a fulminant course of HDV infection is possible in both variants.
In CHD, depending on the replication level of HDV and HBV, 3 variants of viral persistence can be observed: 1) high levels of HDV RNA and low, down to undetectable, levels of HBV DNA in the blood (characteristic suppression of HBV replication in the presence of HDV) — the most frequent variant (2/3 of patients), typical for HBeAg-negative hepatitis; 2) equal levels of HDV RNA and HBV DNA (about 1/3 of patients), mainly in HBeAg-positive hepatitis; 3) high levels of HBV DNA and low levels of HDV RNA — a rarely occurring variant.
CHD is the most severe form of chronic viral hepatitis with an unfavorable prognosis in the majority of patients, characterized predominantly by a progressive course with a significantly faster development of LC (within 1–2 years in 15% of patients, within 5–10 years in 70%) compared to hepatitis B (5 years in 20%) and C (20 years in 10–20%) [19–23], and a higher risk of hepatic complications compared to chronic hepatitis B, such as HCC (3.8-fold), hepatic failure (3.8-fold), death (3.0-fold), and liver transplantation (7.1-fold), according to a meta-analysis of 12 studies [19], as well as a higher frequency of comorbid conditions (hepatitis C, HIV infection, intravenous drug use, smoking, alcohol abuse, mental disorders, arterial hypertension, chronic kidney disease). CHD is currently a leading cause of mortality due to hepatic complications in patients with HIV coinfection [24].
The presence of HDV RNA viremia is the leading factor in mortality caused by the development of hepatic complications (hepatic failure, HCC). Therefore, the main goal of CHD treatment is to suppress HDV RNA viremia aimed at improving the prognosis of the disease [19–21].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Criteria for establishing the diagnosis/condition: The diagnosis of CHD is established in the presence of hepatitis B surface antigen (HBsAg), antibodies to hepatitis D virus (anti-HDV), hepatitis D virus RNA (HDV RNA) detected by PCR, and clinical and laboratory signs of liver damage for 6 months or more.
It is recommended to test all individuals with HBsAg in the blood for antibodies to hepatitis D virus (anti-HDV), regardless of the blood HBV DNA level, aminotransferase activity, or presence of symptoms, for the diagnosis of CHD [1–7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
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.
2.1 Complaints and Anamnesis
It is recommended to evaluate all individuals with suspected CHD for a history of HBV, HDV (including among relatives), HCV, or HIV infection, and risk factors for HDV acquisition (blood or blood product transfusions, surgeries, hemodialysis, intravenous drug use, risky sexual behavior, including among men who have sex with men) to determine the source of infection, transmission routes, and duration of infection [1–7, 16].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
2.2 Physical Examination
It is recommended to assess individuals with suspected CHD for signs of cirrhosis and its complications (portal hypertension — esophageal varices), and hepatic failure (hepatic encephalopathy, ascites, edema, hemorrhagic syndrome) to evaluate the stage and severity of the disease [1–7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
2.3 Laboratory Diagnostics
Diagnosis stage
It is recommended to perform a complete blood count (CBC) with differential leukocyte count and platelet count in all patients with CHD to detect abnormalities (cytopenia) [1, 7].
It is recommended to perform a routine urinalysis in all patients with CHD to detect extrahepatic manifestations (renal involvement) [1].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine blood levels of total, conjugated, and unconjugated bilirubin, albumin, urea, creatinine, glucose, and to measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) activity in the blood of all patients with CHD to assess the presence and severity of hepatic syndromes (cytolysis, cholestasis, hepatic failure), the severity of liver cirrhosis according to the Child-Pugh score, and the presence of comorbid conditions [1–7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine prothrombin time in blood or plasma and/or the international normalized ratio (INR) in all CHD patients at the liver cirrhosis stage to assess the severity of liver cirrhosis according to the Child-Pugh classification [1–7, 25, 26].
It is recommended to test all patients with CHD for antibodies to hepatitis D virus (anti-HDV) in the blood to confirm the etiology of the disease [1–7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) who test positive for antibodies to hepatitis D virus (anti-HDV) in the blood undergo qualitative PCR testing for hepatitis D virus RNA (HDV RNA) in the blood (hereinafter referred to as high-sensitivity testing, ≤ 5 IU/mL, if available) to detect HDV replication, including in cases of chronic hepatitis B with high activity and absent HBsAg [1, 4-7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with CHD and severe fibrosis and liver cirrhosis (F3–F4 by METAVIR) undergo a serum alpha-fetoprotein test to screen for hepatocellular carcinoma [7, 27].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Pre-treatment stage (etiotropic/antiviral therapy)
It is recommended that patients with CHD who test positive for hepatitis D virus RNA (HDV RNA) in the blood by qualitative PCR, prior to initiating etiotropic (antiviral) treatment, undergo quantitative PCR testing for hepatitis D virus RNA (HDV RNA) in the blood (if available) to monitor the virological efficacy of treatment [7, 28-34].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended that patients with CHD, prior to initiating etiotropic (antiviral) therapy with interferons, undergo testing for thyroid peroxidase antibodies (anti-TPO), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) in the blood to detect autoimmune disorders and determine contraindications to treatment [1, 35, 36].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Stage of etiotropic (antiviral) treatment
It is recommended that patients with CHD receiving etiotropic (antiviral) monotherapy undergo a complete blood count (CBC) with differential white blood cell count and platelet count at 4 weeks and every 12 weeks thereafter (or every 4 weeks in the presence of liver cirrhosis) (or more frequently as clinically indicated) to monitor treatment safety and detect cytopenias [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with CHD receiving etiotropic (antiviral) combination therapy undergo a complete blood count (CBC) with differential white blood cell count and platelet count at 2 weeks and every 4 weeks of treatment thereafter to monitor treatment safety and detect cytopenias [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with CHD receiving etiotropic (antiviral) monotherapy or combination therapy undergo testing for total, conjugated (direct), and unconjugated (indirect) bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) in the blood at 4 weeks and every 12 weeks thereafter (or every 4 weeks in the presence of liver cirrhosis) (or more frequently as clinically indicated) to monitor treatment efficacy (biochemical response) and safety [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with CHD receiving etiotropic (antiviral) therapy with interferons undergo testing for thyroid peroxidase antibodies (anti-TPO), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) in the blood every 12 weeks of treatment to detect autoimmune disorders [1, 35, 36].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that patients with CHD and mild-to-moderate liver fibrosis (F0–F2 by METAVIR) receiving etiotropic (antiviral) treatment undergo qualitative PCR testing for hepatitis D virus RNA (HDV RNA) in the blood at 12 weeks of treatment to assess for an early complete virological response (cVR-12); if cVR-12 is achieved, qualitative PCR testing for hepatitis D virus RNA (HDV RNA) in the blood should be performed at 24 and 48 weeks of treatment to detect cVR-24 and cVR-48 [28-34, 42, 52, 63, 64].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended for patients with chronic hepatitis D (CHD) with severe fibrosis and liver cirrhosis (METAVIR F3-F4) receiving etiotropic (antiviral) treatment, qualitative PCR testing for Hepatitis D virus RNA (HDV RNA) in the blood at 48 weeks of treatment to detect post-treatment virological response at week 48 (SVR48); in the absence of SVR48, quantitative PCR testing for Hepatitis D virus RNA (HDV RNA) in the blood (if available) to detect virological response, including partial response (VR-48, pVR-48); in the absence of SVR48, VR-48, pVR-48 – determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in the blood to detect biochemical response (BR-48) [28-34, 37-47, 49, 64].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended for patients with CHD continuing etiotropic (antiviral) treatment for more than 48 weeks, qualitative PCR testing for Hepatitis D virus RNA (HDV RNA) in the blood, 1 time per year (at 96 and 144 weeks from the start of treatment) to detect SVR96, SVR144 [7, 28-34, 50-56, 57, 62].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended for patients with CHD without SVR96 or SVR144 – quantitative PCR testing for Hepatitis D virus RNA (HDV RNA) in the blood (if available) to detect VR-96, VR-144 [28-34, 50-55, 57, 62, 64].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended for patients with CHD receiving combination etiotropic (antiviral) therapy, determination of Hepatitis B virus surface antigen (HBsAg) and antibodies to Hepatitis B virus surface antigen (anti-HBs) in the blood at 48 weeks of treatment, then 1 time per year to detect serological response [7, 38, 57-62].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended for patients with CHD and Child-Pugh class B decompensated liver cirrhosis receiving monotherapy etiotropic (antiviral) treatment, every 4 weeks complete blood count with differential white blood cell count (leukocyte formula) and platelet count determination to monitor treatment safety [1, 42, 43, 47, 71-73].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended for patients with CHD and Child-Pugh class B decompensated liver cirrhosis receiving monotherapy etiotropic (antiviral) treatment, every 2 weeks determination of total, conjugated (bound), and unconjugated (free) bilirubin, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) in the blood to monitor treatment efficacy (biochemical response) and liver function [1, 42, 43, 47, 71-73].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended for patients with CHD and Child-Pugh class B decompensated liver cirrhosis receiving monotherapy etiotropic (antiviral) treatment, every 2 weeks determination of prothrombin time in blood or plasma and/or international normalized ratio (INR) to monitor liver function [1, 25, 26, 42, 43, 47, 71-73].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Post-etiotropic (antiviral) treatment stage
It is recommended for patients with CHD whose etiotropic (antiviral) treatment is discontinued at 48 weeks due to lack of response, determination of alanine aminotransferase (ALT) activity in the blood every 4 weeks for 3 months after discontinuation, to detect an increase in ALT activity due to HDV or HBV reactivation and to determine further management strategy [38, 74].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended for patients with CHD whose etiotropic (antiviral) treatment was discontinued at 48 weeks due to lack of response, who experience an increase in blood alanine aminotransferase (ALT) activity within 3 months after treatment discontinuation, quantitative PCR testing for Hepatitis B virus DNA (HBV DNA) in the blood and quantitative PCR testing for Hepatitis D virus RNA (HDV RNA) in the blood (if available) to detect HDV or HBV reactivation; if no increase in blood alanine aminotransferase (ALT) activity occurs within 3 months after treatment discontinuation, additional virological tests during this period are not required [28, 29, 31-34, 38, 75].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Dispensary monitoring stage
It is recommended for patients with CHD who have completed etiotropic (antiviral) treatment, qualitative PCR testing for Hepatitis D virus RNA (HDV RNA) in the blood 2 times a year to monitor the disease course, treatment efficacy (sustained SVR), and rule out relapse [7, 28, 29, 31-34, 53, 54, 75].
It is recommended for patients with CHD who have completed etiotropic (antiviral) treatment, determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in the blood 2 times a year to monitor the disease course, treatment efficacy (sustained biochemical response [BR] – normalization of aminotransferase activity), and rule out relapse [7, 53, 54, 74, 75].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) who have completed etiotropic (antiviral) treatment undergo blood testing for Hepatitis B virus surface antigen (HBsAg) 1 time per year after completion of treatment to monitor the course of the disease [7, 53, 54, 57, 62].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) with advanced fibrosis and liver cirrhosis (METAVIR F3-F4) undergo serum alpha-fetoprotein testing 2 times per year for hepatocellular carcinoma screening [7, 27].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
2.4 Instrumental Diagnostics
Stage of diagnosis establishment
It is recommended that patients with chronic hepatitis D (CHD) undergo abdominal ultrasound (comprehensive) to assess the stage of the disease and detect focal liver lesions [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) undergo non-invasive assessment of liver fibrosis severity: Liver elastography (controlled attenuation/vibration transient, real-time shear wave, compression/static) and/or calculation of fibrosis indexes (APRI, FIB-4) to assess the stage of the disease [1, 7, 50, 53, 54, 76, 77, 86].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended that patients with chronic hepatitis D (CHD) with liver cirrhosis undergo esophagogastroduodenoscopy to detect esophageal varices [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) with suspected focal liver lesion based on ultrasound and serum alpha-fetoprotein testing undergo contrast-enhanced computed tomography (CT) of the abdominal organs with intravenous bolus injection and/or magnetic resonance imaging (MRI) of the abdominal organs with intravenous administration of a hepatotropic contrast agent (gadoxetic acid**) to clarify the nature of the changes [1, 7, 27].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Stage of etiotropic (antiviral) treatment
It is recommended that patients with chronic hepatitis D (CHD) receiving etiotropic (antiviral) treatment who lack cVR-48, vVR-48, pVR-48, and bVR-48 undergo non-invasive assessment of liver fibrosis severity: Liver elastography (controlled vibration transient, real-time shear wave, compression/static) and/or calculation of fibrosis indexes (APRI, FIB-4) to detect a decrease in liver stiffness and fibrosis indexes [1, 7, 50, 53, 54, 76, 77, 86].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Stage of dispensary follow-up
It is recommended that patients with chronic hepatitis D (CHD) with mild and moderate liver fibrosis (METAVIR F0-F2) undergo abdominal ultrasound (comprehensive) 1 time per year to monitor the development of complications and screen for HCC [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) with advanced fibrosis and liver cirrhosis (METAVIR F3-F4) undergo abdominal ultrasound (comprehensive) 2 times per year to monitor the development of complications and screen for HCC [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) undergo non-invasive assessment of liver fibrosis severity: Liver elastography (controlled vibration transient, real-time shear wave, compression/static) and/or calculation of fibrosis indexes (APRI, FIB-4) 1 time per year to evaluate the dynamics of liver fibrosis [1, 7, 50, 53, 54, 76, 77, 86].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended that patients with chronic hepatitis D (CHD) with esophageal varices undergo esophagogastroduodenoscopy 1 time per year (or more frequently as clinically indicated) to assess the dynamics of variceal grade [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) with suspected focal liver lesion based on ultrasound and serum alpha-fetoprotein testing undergo contrast-enhanced computed tomography (CT) of the abdominal organs with intravenous bolus injection and/or magnetic resonance imaging (MRI) of the abdominal organs with intravenous administration of a hepatotropic contrast agent (gadoxetic acid**) to clarify the nature of the changes [1, 7, 27].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
2.5 Other Procedures
Stage of pre-etiotropic (antiviral) treatment evaluation
It is recommended that patients with chronic hepatitis D (CHD) for whom interferon therapy is planned undergo consultations with specialist physicians—endocrinologist, ophthalmologist, psychiatrist—to ensure treatment safety [1].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with chronic hepatitis D (CHD) undergo percutaneous liver biopsy and pathomorphological examination of liver biopsy (surgical) material using histochemical methods as clinically indicated to clarify the activity of liver injury and the stage of fibrosis (in case of discordant results of abdominal ultrasound, liver elastography, and fibrosis index calculation), and for differential diagnosis with other liver diseases [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
3.1.1 Etiotropic (antiviral) treatment
Indications for initiating etiotropic (antiviral) treatment
• Presence of HDV RNA in the blood
• Patient's consent to antiviral therapy
• Negative pregnancy test
• Absence of contraindications to the medications.
Types of response when evaluating the efficacy of etiotropic (antiviral) treatment
1. Virological response (VR) – a decrease in HDV RNA levels by 2 or more log10 compared to baseline during treatment, indicating the time point of response assessment in weeks (e.g., at 48 weeks from treatment initiation – VR-48);
2. Complete virological response (cVR) – a decrease in HDV RNA levels to undetectable levels (aviremia) during treatment, indicating the time point of response assessment in weeks (e.g., at 48 weeks from treatment initiation – cVR-48);
3. Partial virological response (pVR) – a decrease in HDV RNA levels by 1 log10 or more, but less than 2 log10, compared to baseline, indicating the time point of response assessment in weeks (e.g., at 48 weeks from treatment initiation – pVR-48);
4. Biochemical response (BR) – a decrease or normalization of blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity compared to baseline, indicating the time point of response assessment in weeks (e.g., at 48 weeks from treatment initiation – BR-48);
5. Decrease in liver stiffness on elastography and in fibrosis indexes (APRI, FIB-4).
Etiotropic (antiviral) treatment
• Bulevirtide** is the first and only drug approved for the treatment of chronic hepatitis D (CHD), an entry inhibitor of HBV and HDV into the cell, a blocker of NTCP (sodium taurocholate co-transporting polypeptide – a bile acid transporter and simultaneously the entry receptor for HBV and HDV into the cell) [9–12], included in international and national clinical guidelines for the treatment of chronic hepatitis D (CHD) [7, 72, 83–85].
• Conducted multicenter randomized phase 2 and 3 studies and real-world studies have demonstrated:
− the highest rate of virological response with combination therapy of bulevirtide** 2 mg once daily with #peginterferon alfa-2a (40 kDa)** 180 mcg once weekly for 48 weeks [38, 57]
− increased efficacy of bulevirtide** monotherapy 2 mg once daily with continued treatment up to 96–144 weeks [50–55], including in patients with a partial response and non-response at 24 weeks of treatment (decrease in HDV RNA levels of less than 2 log10 and 1 log10 from baseline) [51],
− comparability of virological response between monotherapy and combination therapy at 96 weeks of treatment [52],
− virological response in the liver (disappearance of HDV RNA and delta antigen from hepatocytes) [66], histological response (absence of progression or reduction in the degree of necrosis, inflammation, and fibrosis) [67] according to repeat biopsies,
− superiority of bulevirtide** monotherapy 2 mg once daily and combination therapy of bulevirtide** 2 mg once daily with #peginterferon alfa-2a (40 kDa)** 180 mcg once weekly over #peginterferon alfa-2a (40 kDa)** monotherapy 180 mcg once weekly regarding virological and biochemical response [38],
− the possibility of a sustained response at 24–48 weeks after the completion of a 48–96 week treatment course [38, 39, 57, 62],
− absence of resistance risk at 96 weeks of monotherapy [87–89],
− the possibility of effective re-treatment with monotherapy or combination therapy in case of relapse after treatment completion (with re-achievement of aviremia) [90],
− the predictive value of an early decrease in HDV RNA levels during treatment (by 2 log10 at 12 weeks) for achieving aviremia at 72 and 96 weeks of treatment [52], and of early and sustained aviremia for the absence of relapses after treatment completion [57, 62–64],
− independence of the biochemical response (decrease or normalization of blood alanine aminotransferase (ALT) activity) and the reduction in non-invasive fibrosis markers (liver stiffness on elastography, APRI and FIB-4 fibrosis indexes) from the virological response [65, 86],
− safety and good tolerability of long-term monotherapy (96–144 weeks of treatment) [50, 52–55, 69],
− improvement in quality of life indicators (physical and mental health) after 48 weeks of monotherapy [70],
− improvement of liver function in decompensated cirrhosis with transition from Child-Pugh class B to class A, comparability of efficacy regarding virological and biochemical response in decompensated and compensated cirrhosis [42, 43, 47, 71-73],
− comparability of efficacy regarding virological and biochemical response in HIV/HDV co-infection and HDV monoinfection [81-83].
• The duration of treatment is determined by the achievement of treatment goals, primarily virological response (HDV RNA viremia clearance), and continues to be evaluated in clinical trials with a treatment duration of at least 144 weeks and a post-treatment follow-up of at least 96 weeks.
**Included in the List of Vital and Essential Drugs
# Used for an off-label indication
It is recommended to prescribe bulevirtide monotherapy for 48 weeks, followed by either discontinuation or continuation of treatment depending on the fibrosis stage and treatment response, to patients with chronic hepatitis D (CHD), including those with compensated liver cirrhosis (Child-Pugh class A), who have contraindications to or intolerance of interferons, in order to achieve a virological, biochemical, or combined response [7, 8, 38-56, 66-68, 84, 85].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Comments: treatment regimen: bulevirtide** 2 mg once daily subcutaneously [7, 8, 37-56, 66-68, 84, 85].
It is recommended to prescribe combination therapy with bulevirtide** and #peginterferon alfa-2a (40 kDa)** for the first 48 weeks, followed by either discontinuation or continuation of treatment depending on the fibrosis stage and treatment response, to patients with CHD, including those with compensated liver cirrhosis (Child-Pugh class A), who have no contraindications to or intolerance of interferons, in order to achieve a virological, biochemical, combined, or serological response [7, 8, 38, 39, 41, 42, 44-47, 52, 57, 62, 84, 85].
GCR BLOC 2Recommendation Grade B (Level of Evidence - 2
Comment: treatment regimen: bulevirtide** 2 mg once daily s.c. + #peginterferon alfa-2a (40 kDa)** 180 mcg once weekly s.c. [38, 57]; adding #peginterferon alfa-2a (40 kDa)** at any stage during the first 48 weeks of bulevirtide** monotherapy is possible to increase treatment efficacy [91].
It is recommended to prescribe combination therapy with bulevirtide** and #peginterferon alfa-2b** for the first 48 weeks, followed by either discontinuation or continuation of treatment depending on the fibrosis stage and treatment response, to patients with CHD, including those with compensated liver cirrhosis (Child-Pugh class A), who have no contraindications to or intolerance of interferons, in order to achieve a virological, biochemical, combined, or serological response [42, 46].
GCR CLOC 4Recommendation Grade C (Level of Evidence - 4
Comment: treatment regimen: bulevirtide** 2 mg once daily s.c. + #peginterferon alfa-2b** 1.0 to 1.5 mcg/kg once weekly s.c. (used in clinical practice [42] with indication that the dosing regimen complies with the instructions for medical use of the medicinal product #peginterferon alfa-2b** for the indication of chronic hepatitis B) [79, 80].
It is recommended to discontinue treatment at 48 weeks, followed by clinical follow-up to monitor treatment efficacy (sustained virological response, biochemical response – normalization of aminotransferase activity), in patients with CHD with mild to moderate liver fibrosis (METAVIR F0-F2), who have achieved all 4 types of response (s12-week, s24-week, and s48-week virological response, and 48-week biochemical response) [42].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to continue long-term treatment for at least 144 weeks from baseline to achieve treatment goals in patients with CHD with mild to moderate liver fibrosis (METAVIR F0-F2) who lack a 12-week virological response, but have a 48-week virological response, 48-week virological response, 48-week biochemical response, or a reduction in non-invasive markers of fibrosis (liver stiffness by elastography, fibrosis indices (FIB-4, APRI) at 48 weeks) [50-57, 62, 69].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended to continue treatment beyond 48 weeks, long-term, for at least 144 weeks from baseline to achieve treatment goals in patients with CHD with advanced fibrosis and liver cirrhosis (METAVIR F3-F4) who have a 48-week virological response, virological response, biochemical response, or a reduction in non-invasive markers of fibrosis (liver stiffness by elastography, fibrosis indices (FIB-4, APRI)) at 48 weeks [38-57, 62, 69].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended that patients with CHD receiving combination therapy who achieve a virological response switch to monotherapy for at least 96 weeks (up to a total duration of at least 144 weeks from baseline) after 48 weeks of treatment, or continue combination therapy if well tolerated for another 48 weeks followed by a switch to monotherapy for at least 48 weeks (up to a total duration of at least 144 weeks from baseline) to achieve treatment goals [52, 57, 62].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended to discontinue treatment at 48 weeks (pending results from ongoing studies) in patients with CHD who lack a 48-week virological response, virological response, biochemical response, or a reduction in non-invasive markers of fibrosis (liver stiffness by elastography, fibrosis indices (FIB-4, APRI)) at 48 weeks [42, 43].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
It is recommended to re-treat patients with CHD who completed treatment due to achieving a virological response and biochemical response (normalization of aminotransferase activity) but experienced HDV infection relapse (detection of HDV RNA), given the absence of resistance risk, to achieve treatment goals [87-90].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to continue bulevirtide** treatment in patients with CHD who had a treatment interruption unrelated to bulevirtide intolerance, given the absence of resistance risk, to achieve treatment goals [87-90].
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
It is recommended to prescribe #bulevirtide** monotherapy to patients with CHD with Child-Pugh class B decompensated liver cirrhosis on an individualized basis, considering the risk-benefit ratio, per the decision of the medical organization's medical board, including the use of a low accelerated dose regimen (LADR) if necessary, under long-term monitoring of liver function dynamics to achieve virological and biochemical responses and improve liver function parameters [43, 47, 71-73, 100].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: treatment regimen: #bulevirtide** 2 mg once daily s.c. [43, 47, 71, 72]; low accelerated dose regimen: #bulevirtide** 2 mg s.c. twice weekly for 8-12 weeks, then 3 times weekly for 8-12 weeks, then once daily [73].
# Used for an off-label indication
It is recommended to continue #bulevirtide** monotherapy in patients with CHD with compensated liver cirrhosis who in isolated cases develop decompensation during etiotropic (antiviral) treatment, considering the absence of a link between decompensation and treatment in clinical trials, including the use of a low accelerated dose regimen (LADR) if necessary, under monitoring of liver function parameters to achieve treatment goals and improve liver function parameters [43, 47, 71-73].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
Comments: treatment regimen: bulevirtide** 2 mg once daily s.c. [43, 47, 71, 72]; low accelerated dose regimen: #bulevirtide** 2 mg s.c. twice weekly for 8-12 weeks, then 3 times weekly for 8-12 weeks, then once daily [73].
# Used for an off-label indication
It is not recommended to use nucleoside and nucleotide reverse transcriptase inhibitors (INN tenofovir**, entecavir**) for the treatment of CHD due to inefficacy [7, 85, 92].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to use nucleoside and nucleotide reverse transcriptase inhibitors (INN tenofovir**, entecavir**) in patients with CHD only if there are indications for treatment of CHB (when HBV DNA levels are >2000 IU/mL in the absence of cirrhosis, in compensated cirrhosis with detectable HBV DNA in blood, and in decompensated cirrhosis both with and without detectable HBV DNA in blood) [7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to use the same regimens for HIV-infected patients with CHD as for HDV monoinfection, taking into account drug-drug interactions with direct-acting antivirals for HIV infection [81-83].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to consider the use of telemedicine technologies to monitor treatment efficacy and safety in patients with CHD receiving etiotropic (antiviral) treatment, based on the attending physician's decision, regardless of the care delivery setting [93-95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
3.1.2 Symptomatic Treatment
It is recommended to reduce the dose of interferons in accordance with the instructions for medical use of the medicinal product in patients with CHD who develop interferon-induced leukopenia and thrombocytopenia [1].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3.2 Surgical Treatment
It is recommended to perform liver transplantation in patients with CHD with persistent liver function decompensation [1, 7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: additional evaluation is performed at a transplantation center in accordance with the management protocol for patients on the waiting list.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Rehabilitation measures have not been developed.
5. Prevention and Dispensary Observation
5.1 Follow-up care
It is recommended that patients with chronic hepatitis D (CHVD) undergo dispensary follow-up (examinations, consultations) by an infectious disease specialist, general practitioner (family physician), general physician, or gastroenterologist at a medical organization near their place of residence or at a territorial specialized center [1].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with CHVD, following the completion of etiotropic (antiviral) treatment, receive ongoing monitoring by an infectious disease specialist, general practitioner (family physician), general physician, or gastroenterologist with an evaluation frequency of twice a year (or more frequently if indicated) [1].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
5.2 Prevention
5.2.1 Specific prevention
It is recommended that all persons receive the vaccine for prevention of viral hepatitis B** in accordance with the national preventive vaccination schedule and the preventive vaccination schedule for epidemic indications, to prevent the development of HDV infection [7, 96, 97].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: Hepatitis B vaccine**
The standard 0-1-6 month vaccination schedule involves administering the first dose at the maternity hospital, the second dose at 1 month of age, and the third dose no earlier than 5 months later (at 6 months of age). In older children and adults, the second dose is administered 1 month after the first, and the third dose 5 months later, strictly adhering to the established intervals between doses. For children in risk groups (presence of chronic hepatitis B in the mother or a family member, presence of HBsAg in the mother, lack of screening of the mother during pregnancy, socially disadvantaged family), the vaccination schedule is 0-1-2-12 months. For emergency prophylaxis (including in infants born to HBsAg-positive mothers), the vaccination schedule is 0-1-2-12 months.
**Included in the VLEL list (Vital and Essential Drugs)
It is recommended that patients with CHVD who lack anti-hepatitis A antibodies in their blood serum receive the hepatitis A vaccine** to prevent hepatitis A virus infection [1, 98].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
5.2.2 Non-specific prophylaxis
It is recommended to actively identify sources of infection (screening individuals at increased risk of infection and/or of epidemiological significance) [14-16].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
It is recommended to prevent the artificial transmission route (blood transfusions for life-saving indications, justification of invasive diagnostic methods, use of disposable instruments, strict adherence to processing protocols for medical instruments and equipment, and use of personal protective equipment by medical personnel) [1].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with CHVD receive etiotropic (antiviral) treatment aimed at HDV eradication [99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
6. Organization of Medical Care
Medical care for patients with CHVD is provided:
in outpatient settings that do not require round-the-clock medical monitoring and treatment;
in day hospital settings that do not require round-the-clock medical monitoring and treatment, but provide medical supervision and treatment during the daytime;
in inpatient settings providing round-the-clock medical monitoring and treatment.
Medical care for patients with CHVD is provided as part of primary health care in outpatient and day hospital settings by infectious disease specialists, general practitioners (family physicians), general physicians, and gastroenterologists; and as part of specialized medical care in inpatient and day hospital settings by infectious disease specialists, gastroenterologists, and other medical specialists.
Patients with CHVD must remain under lifelong follow-up.
7. Additional Information
Risk factors for liver failure and death [1]:
• presence of HDV RNA in the blood [19-21],
• co-infection (other hepatotropic viruses, human immunodeficiency virus) [24],
• alcoholism, substance abuse, toxicomania, metabolic dysfunction-associated steatotic liver disease,
• drug-induced liver injury,
• comorbid chronic conditions (diabetes mellitus, obesity, blood disorders, others),
• immunodeficiencies,
• alimentary dystrophy.
Factors negatively affecting the efficacy of etiotropic (antiviral) treatment [1]:
• presence of liver cirrhosis [52],
• development of adverse events requiring treatment discontinuation.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance evaluation (yes/no) |
Diagnosis stage | ||
1. | Complete blood count (CBC) with differential (leukocyte formula) and platelet count performed | Yes/no |
2. | Assay of total bilirubin, conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, albumin, urea, creatinine, blood glucose, and determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) activity in the blood performed | Yes/no |
3. | Determination of prothrombin time in blood or plasma and/or International Normalized Ratio (INR) performed | Yes/no |
4. | Determination of antibodies to hepatitis D virus (anti-HDV) in the blood performed | Yes/no |
5. | Qualitative determination of hepatitis D virus (HDV) RNA in the blood by PCR (hereinafter referred to as high sensitivity, $\le$ 5 IU/ml, if available) performed | Yes/no |
6. | Assay of serum alpha-fetoprotein in patients with advanced liver fibrosis and cirrhosis (F3-F4 by METAVIR) performed | Yes/no |
7. | Abdominal ultrasound (comprehensive) performed | Yes/no |
8. | Non-invasive assessment of liver fibrosis severity: liver elastography (controlled attenuation parameter/vibration-controlled transient elastography, real-time shear wave elastography, or real-time compression elastography) and/or calculation of fibrosis scores (APRI, FIB-4) performed | Yes/no |
9. | Esophagogastroduodenoscopy performed in patients with liver cirrhosis and portal hypertension | Yes/no |
10. | Abdominal CT with intravenous bolus contrast enhancement and/or abdominal MRI with intravenous administration of a hepatotropic contrast agent (gadoxetic acid) performed when a focal liver lesion is suspected | Yes/no |
Pre-treatment stage (etiotropic/antiviral therapy) | Yes/no | |
11. | Quantitative determination of hepatitis D virus (HDV) RNA in the blood by PCR (if available) performed | Yes/no |
12. | Testing for anti-thyroperoxidase (anti-TPO) antibodies, free thyroxine (fT4), and thyroid-stimulating hormone (TSH) in blood serum performed prior to interferon therapy | Yes/no |
Stage of etiotropic (antiviral) treatment | ||
13. | Treatment with bulevirtide** as monotherapy or combination therapy with interferons performed | Yes/no |
14. | Complete blood count (CBC) with differential (leukocyte formula) and platelet count performed at 4 weeks and every 12 weeks of treatment thereafter (or every 4 weeks in the presence of cirrhosis) during monotherapy | Yes/no |
15. | Complete blood count (CBC) with differential (leukocyte formula) and platelet count performed at 2 weeks and every 4 weeks of combination therapy (or more frequently as indicated) | Yes/no |
16. | Assay of total bilirubin, conjugated (direct) bilirubin, unconjugated (indirect) bilirubin in blood, and determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) activity performed at 4 weeks and every 12 weeks of monotherapy or combination therapy thereafter (or every 4 weeks in the presence of cirrhosis) | Yes/no |
17. | Testing for anti-TPO antibodies, free thyroxine (fT4), and thyroid-stimulating hormone (TSH) in blood serum performed every 12 weeks of interferon therapy (или чаще по показаниям) | Yes/no |
18. | Qualitative determination of hepatitis D virus (HDV) RNA in the blood by PCR performed in patients with mild to moderate liver fibrosis (F0-F2 by METAVIR) at 12, 24, and 48 weeks of treatment | Yes/no |
19. | Qualitative determination of hepatitis D virus (HDV) RNA in the blood by PCR performed in patients with advanced fibrosis and liver cirrhosis (F3-F4 by METAVIR) at 48 weeks of treatment; if positive, quantitative determination of hepatitis D virus (HDV) RNA in the blood by PCR (if available) and determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in the blood performed at 48 weeks of treatment | Yes/no |
20. | Qualitative determination of hepatitis D virus (HDV) RNA in the blood by PCR performed at 96 and 144 weeks from the start of treatment; if positive, quantitative determination of hepatitis D virus (HDV) RNA in the blood by PCR (if available) performed | Yes/no |
21. | Non-invasive assessment of liver fibrosis severity: liver elastography (controlled vibration-controlled transient, dynamic ultrasound shear-wave, or real-time compression elastography) and/or calculation of fibrosis scores (APRI, FIB-4) performed at 48 weeks of treatment in patients lacking virological, complete virological, partial virological, or biochemical response | Yes/no |
22. | Performed in patients receiving combination therapy: Determination of hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) in blood, antibodies to hepatitis B virus surface antigen (HBsAg) in blood at 48 weeks of treatment, then once a year | Yes/no |
23. | Performed in patients with decompensated liver cirrhosis receiving monotherapy every 4 weeks: Complete blood count (CBC) with differential, Platelet count | Yes/no |
24. | Performed in patients with decompensated liver cirrhosis receiving monotherapy every 2 weeks: Determination of total, conjugated (direct), and unconjugated (indirect) bilirubin, albumin in blood, determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) activity in blood | Yes/no |
25. | Performed in patients with decompensated liver cirrhosis receiving monotherapy: Determination of prothrombin time in blood or plasma and/or International Normalized Ratio (INR) | Yes/no |
Post-etiotropic (antiviral) treatment stage | ||
26. | Performed in patients who discontinued treatment due to lack of response: Determination of alanine aminotransferase (ALT) activity in blood every 4 weeks for 3 months after discontinuation | Yes/no |
27. | Performed in patients who discontinued treatment due to lack of response: Quantitative PCR assay for Hepatitis B virus DNA (HBV DNA) in blood, quantitative PCR assay for Hepatitis D virus RNA (HDV RNA) in blood (if available) | Yes/no |
Dispensary monitoring stage | ||
28. | Performed in patients who completed treatment due to achieving aviremia and normalization of aminotransferase levels: Qualitative PCR assay for Hepatitis D virus RNA (HDV RNA) in blood 2 times a year | Yes/no |
29. | Performed in patients who completed treatment due to achieving aviremia and normalization of aminotransferase levels: Determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in blood 2 times a year | Yes/no |
30. | Performed in patients who completed treatment due to achieving aviremia and normalization of aminotransferase levels: Determination of hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) and antibodies to HBsAg in blood 1 time a year | Yes/no |
31. | Performed in patients with advanced fibrosis and liver cirrhosis (METAVIR F3-F4): Serum alpha-fetoprotein testing 2 times a year | Yes/no |
32. | Performed: Abdominal ultrasound (comprehensive) in patients with mild to moderate liver fibrosis (METAVIR F0-F2) 1 time a year, and in patients with advanced fibrosis and liver cirrhosis (METAVIR F3-F4) – 2 times a year | Yes/no |
33. | Performed: Non-invasive assessment of liver fibrosis severity: Liver elastography (controlled attenuation/vibration transient elastography, real-time shear wave elastography, or real-time compression elastography) and/or calculation of fibrosis scores (APRI, FIB-4) 1 time a year | Yes/no |
34. | Performed: Esophagogastroduodenoscopy in patients with esophageal varices 1 time a year (or more frequently as clinically indicated) | Yes/no |
35. | Abdominal CT with intravenous bolus contrast enhancement and/or abdominal MRI with intravenous administration of a hepatotropic contrast agent (gadoxetic acid) performed when a focal liver lesion is suspected | Yes/no |
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Wedemeyer H, Aleman S, Brunetto M, et al. Bulevirtide monotherapy in patients with chronic HDV: efficacy and safety results through week 96 from a phase 3 randomized trial. J Hepatol. 2024 May 9:S0168-8278(24)00333-7. doi: 10.1016/j.jhep.2024.05.001. Epub ahead of print.
Lampertico P, Wedemeyer H, Brunetto M, et al. Continued treatment of early non-responder or partial virologic responders with bulevirtide monotherapy in patients with chronic hepatitis D through week 96 leads to improvement in virologic and biochemical responses. J Hepatol. 2023, 78, suppl. 1, S113-4, LBP20.
De Ledinghen V., Asselah T., Roulot D. et al. et al. Treatment with bulevirtide, with or without peg-interferon, in HDV infected patients in a real-life setting. Two-year results from the French multicenter early access program. Hepatology. 2022, 76: S26-S28. Available at https://www.natap.org/2022/AASLD/AASLD_80.htm.
Degasperi E, de Lédinghen V, Reiberger T, et al. Virological and clinical outcomes of patients with HDV-related compensated cirrhosis treated with bulevirtide monotherapy: the retrospective multicenter European study (Save-D). J Hepatol. 2023, 78, suppl. 1, S107, LBP-11.
Degasperi E, Anolli M, Jachs M, et al. Long-term virological and clinical outcomes of patients with HDV-related compensated cirrhosis treated with bulevirtide monotherapy for up to 120 weeks: a retrospective multicenter european study (Save-D). J Hepatol. 2024, 80, S793-S794, WED-391. doi: 10.1016/S0168-8278(24)02203-7.
Lampertico P, Aleman S, Brunetto M, et al. Efficacy and safety of 144 weeks of bulevirtide 2 mg or 10 mg monotherapy from the ongoing phase 3 study, MYR301. J Hepatol. 2024, 80, S92, LBP-029. doi: 10.1016/S0168-8278(24)00596-8.
Anolli MP, Degasperi E, Allweiss L, et al. A 3-year course of bulevirtide monotherapy may cure HDV infection in cirrhotics. J Hepatol. 2023 Jan 3:S0168-8278(22)03475-4. doi: 10.1016/j.jhep.2022.12.023.
Asselah T, Chulanov V, Lampertico P, et al. Bulevirtide combined with pegylated interferon for chronic hepatitis D. N Engl J Med. 2024 Jun 6. doi: 10.1056/NEJMoa2314134. Epub ahead of print.
Wedemeyer H., Yurdaydìn C., Dalekos et al. HIDIT Study Group. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med, 2011, 364: 322-31.
Heidrich B., Yurdaydın C., Kabaçam G. et al. HIDIT-1 Study Group. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014, 60: 87-97.
Wedemeyer H., Yurdaydin C., Hardtke S. et al. HIDIT-II study team. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis. 2019, 19: 275-86.
Bremer B., Anastasiou O., Hardtke S. et al. Residual low HDV viremia is associated with HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis D (delta): results from the HIDIT-II study. J Hepatol. 2020, 73, suppl. 1: S868.
Asselah T, Chulanov V, Lampertico P, et al. 48-week off-therapy efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in patients with chronic hepatitis delta: final results from the phase 2b, open-label, randomised, multicentre study MYR204. J Hepatol. 2024, 80, S1-S2. GS-002. doi:10.1016/S0168-8278(24)00425-2.
Zoulim F, Chulanov V, Lampertico P, et al. Undetectable HDV RNA at 24 weeks of treatment with combination therapy is an important predictor of maintained response off-therapy. J Hepatol. 2024, 80, S764. FRI-371. doi:10.1016/S0168-8278(24)02136-6.
Zoulim F, Asselah T, Chulanov V, et al. Undetectable hepatitis delta virus RNA at the end of treatment with bulevirtide and pegylated interferon alpha-2a is an important predictor of 48 weeks sustained virologic response in chronic hepatitis delta. J Hepatol. 2024, 80, S796, WED-395. doi:10.1016/S0168-8278(24)02207-4.
Dietz-Fricke C, Tacke F, Zöllner C, et al. Treating hepatitis D with bulevirtide - Real-world experience from 114 patients. JHEP Rep. 2023 Mar 15;5(4):100686. doi: 10.1016/j.jhepr.2023.100686.
Allweiss L, Volmari A, Suri V, et al. Blocking viral entry with bulevirtide reduces the number of HDV-infected hepatocytes in human liver biopsies. J Hepatol. 2024 Jun;80(6):882-891. doi: 10.1016/j.jhep.2024.01.035. Epub 2024 Feb 8.
Lampertico P, Aleman S, Bogomolov P, et al. Improvement in liver histology is observed in most patients with chronic hepatitis delta after 48 weeks of bulevirtide monotherapy. J Hepatol. 2024, 80, S794, WED-392. doi: 10.1016/S0168-8278(24)02204-9.
Lampertico P, Brunetto M, Buti M, et al. Impact of bulevirtide given with or without nucleos (t)ide analogues on 48-week virologic outcomes in patients with chronic hepatitis delta virus infection. J Hepatol. 2024, 80, S758, TOP-400. doi:10.1016/S0168-8278(24)02124-X.
Aleman S, Wedemeyer H, Brunetto M, et al. High rates of adherence to bulevirtide monotherapy for chronic hepatitis delta through 96 weeks: results from an interim analysis of the phase 3 study MYR301. Gastroenterology. 2024, 166, S-1603, Sa1626. doi:10.1016/S0016-5085(24)04142-8.
Buti M., Wedemeyer H., Aleman S., et al. Treatment with bulevirtide improves patient reported outcomes in patients with chronic hepatitis delta (CHD): an exploratory analysis of a phase 3 trial at 48 weeks. J Hepatol., 2022, 77, suppl.1: S103, OS149.
Dietz-Fricke C, Degasperi E, Jachs M, et al. Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis-A real-world case series. Hepatology. 2024 Mar 13. doi: 10.1097/HEP.0000000000000847. Epub ahead of print.
Sandmann L, Berg T, Deterding K, et al. Antiviral therapy of chronic hepatitis D virus infection - Addendum to the S3 guideline "Prophylaxis, Diagnosis and Therapy of Hepatitis B Virus Infection" of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS). Z Gastroenterol. 2023 Dec;61(12):e715-e732. doi: 10.1055/a-2181-3345. Epub 2023 Dec 11.
Bogomolov P, Bueverov A, Barsukova N, et al. Bulevirtide in patients with non-compensated liver cirrhosis due to hepatitis D. Hepatology. 2023, The Liver Meeting, Boston, Massachusetts, Nov 10-14, 2023, S2142, Abstract 1259-C. Available at https://www.natap.org/2023/AASLD/AASLD_18.htm
Begré L. et al. Long-term trends of alanine aminotransferase levels among persons living with human immunodeficiency virus/hepatitis B virus with and without hepatitis delta coinfection. Frontiers in medicine. 2022, 9, 988356.
Buti M. et al. Clinical outcome of acute and chronic hepatitis delta over time: a long‐term follow‐up study. J Viral Hepat. 2011, 18 (6), 434-442.
Kalkan Ç. et al. Non‐invasive fibrosis markers for assessment of liver fibrosis in chronic hepatitis delta. J Viral Hepat. 2023, 30 (5), 406-416.
Yang A. H. et al. Shear wave elastography: How well does it perform in chronic hepatitis D virus infection? J Viral Hepat. 2022, 29 (12), 1127-1133.
Instructions for medical use of the medicinal product Pegasys, registration number P N013704/01, https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=abc8c083-5b49-4fcc-892b-16dc99051722.
Instructions for medical use of the medicinal product Pegaltevir, registration number LP-002542, https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=3e2b22dd-60df-4316-ab5c-3876edaeda33.
Instructions for medical use of the medicinal product Peginterferon alfa-2b, registration number LP-003437, https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=a750cc86-a205-46d6-ba7c-2d74cf446883.
De Ledinghen V., Zoulim F. et al. Treatment with bulevirtide, with or without PEG-interferon, in HIVHBV/HDV co-infected patients in a real-life setting.
J Hepatol. 2023, 78, suppl. 1, S1161, SAT-185.
Comandini U. et al. “Real world” efficacy of bulevirtide in HBV/HDV-related cirrhosis including people living with HIV: results from the compassionate use programme at INMI Spallanzani in Rome, Italy. HIV Med. 2023, 24: 1075-82.
Ambrosioni J, Levi L, Alagaratnam J, et al; EACS Governing Board. Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023. HIV Med. 2023 Nov;24(11):1126-1136. doi: 10.1111/hiv.13542. Epub 2023 Oct 18.
NICE (National Institute of Care end Excellence). Bulevirtide for treating chronic hepatitis D. Technology appraisal guidance. Published 07 June 2023. Available at https://www.nice.org.uk/guidance/ta896.
World Health Organization. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. 2024, 272 p. Available at https://www.who.int/publications/i/item/9789240090903.
Castera L, Lampertico P, Bogomolov P, et al. Improvement in noninvasive tests (LSM, FIB-4, and APRI) is seen through 96 weeks of bulevirtide monotherapy in CHD regardless of virologic response. Hepatology. 2023;78:S572-4.
Manhas S., Han B., Xu S., Urban S. et al. Bulevirtide is broadly active against all HDV genotypes expressing envelopes from HBV genotypes A-H and a large panel of clinical isolates. J Hepatol., 2022, 77, suppl.1: S244, THU302.
Mateo R., Aeschbacher T., Liu Y. et al. Polymorphic analysis of bulevirtide sequence in PreS1 of large HBsAg across HBV genotypes A-H. J Hepatol. 2022, 77, suppl.1: S247, THU309.
Aleman S, Liu Y, Xu S, et al. No detectable resistance to bulevirtide monotherapy through 96 weeks treatment in patients with chronic hepatitis D. Hepatology. 2023;78:S398-9.
Jachs M, Panzer M, Hartl L, et al. Long-term follow-up of patients discontinuing bulevirtide treatment upon long-term HDV-RNA suppression. JHEP Rep. 2023 Apr 7;5(8):100751. doi: 10.1016/j.jhepr.2023.100751.
Jachs M, Schwarz C, Panzer M, et al. Response-guided long-term treatment of chronic hepatitis D patients with bulevirtide-results of a "real world" study. Aliment Pharmacol Ther. 2022 Jul;56(1):144-154. doi: 10.1111/apt.16945. Epub 2022 May 5.
Scheller L., Hilgard G., Anastasiou O. et al. Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients. Medicine (Baltimore), 2021, 100: e26571.
Barreira Díaz A, Rando A, Feliu-Prius A, et al. LINK-B: study protocol of a retrospective and prospective project for identification and linkage to care of people living with hepatitis B in a large health area of Barcelona. BMJ Open. 2022 Dec 23;12(12):e062680. doi: 10.1136/bmjopen-2022-062680.
Kim RG, McDonell C, McKinney J, et al. Staff-facilitated telemedicine care delivery for treatment of hepatitis c infection among people who inject drugs. Healthcare (Basel). 2024 Mar 25;12(7):715. doi: 10.3390/healthcare12070715.
Rosato V, Nevola R, Conturso V, et al. Telemedicine improves HCV elimination among italian people who use drugs: an innovative therapeutic model to increase the adherence to treatment into addiction care centers evaluated before and during the COVID-19 pandemic. Biology (Basel). 2022 May 24;11(6):800. doi: 10.3390/biology11060800.
Isaeva O.V., Kozhanova T.V., Ilchenko L.Yu. et al. Impact of hepatitis B vaccination on the prevalence of delta hepatitis in an endemic region. Infektsionnye bolezni: novosti, mneniya, obuchenie. 2019, 8: 36-42.
Goyal A., Murray J. The impact of vaccination and antiviral therapy on hepatitis B and hepatitis D epidemiology. PLoS ONE, 2014, 9: e110143.
Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of Hepatitis A Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices, 2020. MMWR Recomm Rep. 2020 Jul 3;69(5):1-38. doi: 10.15585/mmwr.rr6905a1.
Vanwolleghem T, Armstrong PA, Buti M, et al. The elimination of hepatitis D as a public health problem: needs and challenges. J Viral Hepat. 2024 Jan;31(1):47-50.
Meszaros M, Hilleret M, Dumortier J, et al. Bulevirtide efficacy and safety in chronic hepatitis delta patients on liver transplant waiting list. J Hepatol. 2024, 80, S802, FRI-3
Appendix A1. Working Group Composition
Bogomolov, Pavel Olegovich, Candidate of Medical Sciences, Head of the Hepatology Department, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky; Professor of the Hepatology Course, Faculty of Advanced Medical Training, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky;
Zhdanov, Konstantin Valerievich, Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Director of the Pediatric Research and Clinical Center for Infectious Diseases of the Federal Medical-Biological Agency of the Russian Federation;
Ivashkin, Vladimir Trofimovich, Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, President of the Russian Gastroenterological Association, Russian Association for the Study of the Liver, Head of the Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Honored Doctor of the Russian Federation, Honored Scientist of the Russian Federation;
Ilchenko, Lyudmila Yuryevna, Doctor of Medical Sciences, Professor at the Department of Hospital Therapy, N.I. Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation; Leading Researcher at the Laboratory of Viral Hepatitis, I.I. Mechnikov Research Institute of Vaccines and Sera of the Federal Agency of Scientific Organizations (FANO) of Russia; Leading Researcher at the Laboratory of Immunobiological Process Modeling with Experimental Clinic of Marmoset Monkeys, M.P. Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of the Russian Academy of Sciences;
Isaeva, Olga Vladislavovna, Candidate of Biological Sciences, Leading Researcher at the Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation; Leading Researcher at the Laboratory of Viral Hepatitis, I.I. Mechnikov Research Institute of Vaccines and Sera of the Federal Agency of Scientific Organizations (FANO) of Russia; Senior Lecturer at the Department of Virology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation;
Magomedova, Saniyat Akhmedgadzhievna, Candidate of Medical Sciences, Associate Professor at the Department of Infectious Diseases, Dagestan State Medical University of the Ministry of Health of the Russian Federation;
Elena Yu. Malinnikova, MD, PhD, Associate Professor, Head of the Department of Virology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health;
Mikhail I. Mikhailov, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Viral Hepatitis, Mechnikov Research Institute of Vaccines and Sera of the Russian Federal Agency for Scientific Organizations; Scientific Director of the Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health;
Ksenia E. Novak, PhD, Associate Professor, Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health;
Olga I. Sagalova, MD, PhD, Professor of the Department of Infectious Diseases, South-Ural State Medical University of the Russian Ministry of Health;
Snezhana S. Sleptsova, MD, PhD, Associate Professor, Head of the Department of Infectious Diseases, Phthisiology and Dermatovenereology, Medical Institute, Ammosov North-Eastern Federal University of the Ministry of Science and Higher Education of the Russian Federation;
Elena V. Esaulenko, MD, PhD, Professor, Head of the Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health;
Vladimir P. Chulanov, MD, PhD, Professor of the Department of Infectious Diseases, Faculty of Preventive Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health; Deputy Director for Research and Innovative Development, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health.
Conflict of interest: none declared
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
1. infectious disease specialist;
2. gastroenterologist;
3. general practitioner / internist;
4. general practitioner (family physician);
5. medical students, residents, postgraduate students.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | There is only a rationale for the mechanism of action or expert opinion |
Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | There is only a rationale for the mechanism of action of the intervention (preclinical studies) or expert opinion |
Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
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
1. Instructions for medical use of medicinal products, http://grls.rosminzdrav.ru
2. Order of the Ministry of Health and Social Development of the Russian
Federation No. 69n dated January 31, 2012, “On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases”;
3. Order of the Russian Ministry of Health No. 906n dated November 12, 2012, “On Approval ofয়ন the Procedure for Providing Medical Care to the Population in the Profile ‘Gastroenterology’”, registered with the Ministry of Justice of the Russian Federation on January 21, 2013, registration No. 26641;
4. Standard of medical care for adults with chronic hepatitis D, approved by the Ministry of Health on September 27, 2023, No. 501-n, registered with the Ministry of Justice of the Russian Federation on November 3, 2023, registration No. 75841.
Appendix B. Physician Action Algorithms
Diagnostics and determination of indications for etiotropic (antiviral) treatment with bulevirtide**
Algorithm of etiotropic (antiviral) treatment of CHD depending on the fibrosis stage and response to bulevirtide** treatment
Appendix C. Patient Information
Hepatitis D is a liver disease caused by the hepatitis D virus (HDV), which requires the hepatitis B virus (HBV) to replicate. Hepatitis D infection only occurs in the presence of hepatitis B virus.
Prevalence of hepatitis D
At least 5% of people with chronic HBV infection are also infected with HDV. This is only an approximate figure, as many countries do not track the prevalence of hepatitis D.
Routes of transmission of hepatitis D virus
Hepatitis D virus is typically transmitted via contact of non-intact skin and mucous membranes with infected blood or other body fluids. This can occur through blood transfusions, reuse of non-sterile medical instruments, injection drug use, from an infected mother to her child during childbirth, through unprotected sexual contact, and close household contact.
Risk groups for hepatitis D virus infection
• Patients with chronic HBV infection are at the highest risk of infection
• Individuals without immunity to hepatitis B virus (natural, following resolved acute hepatitis B, or acquired, following hepatitis B vaccination)
• Individuals who inject drugs and use non-sterile syringes
• Individuals engaging in high-risk sexual behavior (having casual or multiple sexual partners)
• Patients receiving blood transfusions
• Family members and individuals living in close contact with the patient
• Newborns of infected mothers (transmission during childbirth)
• Healthcare workers
Disclosing the diagnosis to loved ones
Due to established social stereotypes, patients often face undeserved alienation and phobias from others.
It is important to inform close contacts about the disease to raise awareness of potential transmission routes and preventive measures.
Patients are not required to disclose their status to their employer; however, in the event of medical or cosmetic procedures, it is best to inform the medical staff.
Precautions to prevent infection of close contacts
After diagnosis confirmation, it is recommended to immediately vaccinate against hepatitis B individuals who lack immunity to HBV (natural or acquired)—once immunity to HBV is established, the likelihood of coinfection with both viruses (HBV and HDV) is eliminated.
Family members should not share personal items with patients, such as toothbrushes, razors, or nail scissors.
If a patient cuts themselves and needs assistance with wound care, the caregiver must wear gloves to avoid contact with blood.
All minor wounds and cuts of the patient should be covered with a plaster.
If the patient is prescribed injectable treatment, disposable sterile syringes must be used. Needles and items with traces of blood after injection should be discarded into the trash with precautions to prevent accidental injuries to bystanders—immediately after use, they should be placed in a rigid, leak-proof, and puncture-resistant container, kept tightly closed when necessary, and stored out of reach of children and other individuals.
Treatment
Hepatitis D treatment can slow down disease progression; it should be initiated promptly after diagnosis and continued long-term if necessary.
Prevention
The only way to prevent HDV infection in healthy individuals is vaccination for the prevention of viral hepatitis B; however, the vaccine does not protect against HDV in those already infected with HBV.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. Child-Pugh scale for assessing the severity of liver cirrhosis
Source: 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: assessment scale for the severity of liver cirrhosis
Content:
Parameter | Points | ||
1 point | 2 points | 3 points | |
Ascites | absent | mild, manageable with treatment | moderate to severe (refractory) |
Total bilirubin, µmol/L (mg/dL) | <34 (<2) | 34–50 (2–3) | >50 (>3) |
Albumin, g/dL | >3,5 | 2,8–3,5 | <2,8 |
Hepatic encephalopathy | absent | grade 1: mood changes, confusion, grade 2: inappropriate behavior, developing stupor, drowsiness | grade 3: marked confusion, stupor, arousable, grade 4: coma, unresponsiveness |
Prothrombin index (PTI), %, or Prothrombin time (PT), s, or International Normalized Ratio (INR) | >60% or <4.0 s or <1,70 | 40–60% or 4.0–6.0 s or 1,71–2,30 | <40% or >6.0 s or >2,30 |
Points are assigned from 1 to 3 based on the value of each parameter, then summed.
Key (interpretation of the total score):
Child-Pugh class | Score |
|---|---|
A | 5-6 |
C | 7-9 |
C | 10-15 |
Appendix G2. Calculation formulas for fibrosis indices
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):
APRI value | Conclusion | Rating scale |
> 2,0 | F4 | |
≥1,5 | F3-F4 | METAVIR |
0,5 - 1,5 | Equivocal result | |
< 0,5 | F0-F2 | METAVIR |
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, 13 (6), e0199760.
Type: Index
Content: Calculation formula:
FIB-4 = Age (years) × AST / platelets (109/L) × √ALT
Age - patient's age (years)
AST - patient's aspartate aminotransferase value
Platelets (109/L) - patient's platelet count per 1 L of blood
√ALT – square root of the patient's alanine aminotransferase value
Key (interpretation):
FIB-4 value | Conclusion | Rating scale |
> 3,25 | F3-F4 | METAVIR |
< 1,45 | F0-F2 | METAVIR |
1,45 - 3,25 | Equivocal result |
Appendix G3. Etiotropic (antiviral) treatment of chronic viral hepatitis D
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):
F0 | No fibrosis |
F1 | Portal fibrosis with broadening of portal tracts without septa formation |
F2 | Portal fibrosis with rare portoportal septa |
F3 | Numerous portocentral septa without cirrhosis |
F4 | Cirrhosis |