Chronic viral hepatitis C: clinical guidelines

List of Abbreviations

** – indicated at the end of the drug name or drug combination name, meaning they belong to the VED (Vital and Essential Drugs) list

# – indicated at the beginning of the drug name or drug regimen used off-label

Anti-HCV – antibodies to hepatitis C virus

Anti-HBc – antibodies to hepatitis B core antigen

HBcAg – hepatitis B core antigen, hepatitis B core antigen

HBsAg – hepatitis B surface antigen, hepatitis B surface antigen

HBV – hepatitis B virus, hepatitis B virus

HCVcAg – hepatitis C virus core antigen, hepatitis C core antigen

HCV – hepatitis C virus, hepatitis C virus

HIV – human immunodeficiency virus, human immunodeficiency virus

MELD – model for end-liver disease, calculated index characterizing the severity of end-stage liver disease

NS3/4A inhibitors – antiviral agents for the treatment of hepatitis C that block the NS3 and NS4A non-structural proteins of the hepatitis C virus (J05AE Protease inhibitors)

NS5A inhibitors – antiviral agents for the treatment of hepatitis C that block the NS5A non-structural protein of the hepatitis C virus (J05AX Other antivirals)

ALT – alanine aminotransferase

AST – aspartate aminotransferase

AFP – alpha-fetoprotein

HBV – hepatitis B virus

HCV – hepatitis C virus

VEL+SOF** – velpatasvir+sofosbuvir**

VL – viral load

HIV – human immunodeficiency virus

varices – variceal veins

GGT – gamma-glutamyl transferase

GLE+PIB** – glecaprevir+pibrentasvir**

GRA+ELB** – grazoprevir+elbasvir**

GT – genotype

HCC – hepatocellular carcinoma

DCV** – daclatasvir**

DNA – deoxyribonucleic acid

VLEL – vital and essential drugs

LED+SOF – ledipasvir+sofosbuvir

IU – international unit

ICD-10 – International Classification of Diseases, 10th Revision

NRV** – narlaprevir**

NRV**/r** – narlaprevir/ritonavir-boosted**

OLT – orthotopic liver transplantation

PegIFN** – peginterferon alfa-2b**

DAA – direct-acting antivirals

PT – prothrombin index

RBV** – ribavirin**

RNA – ribonucleic acid

QD – once daily

GFR – glomerular filtration rate

SOF** – sofosbuvir**

tab. – tablet

US – ultrasound examination

SVR – sustained virological response

SVR12 – sustained virological response at 12 weeks post-treatment

CKD – chronic kidney disease

CHC – chronic viral hepatitis

LC – liver cirrhosis

Terms and Definitions

Viral load (VL) – the amount of viral RNA in the blood, measured in IU/mL.

Hepatitis C virus genotypes – variants of the hepatitis C virus classified based on nucleotide sequence differences in specific regions of the viral genome. In clinical practice, they are crucial for selecting antiviral treatment regimens when genotype-specific drugs are used.

Hepatitis – inflammation of liver tissue, characterized by necroinflammatory changes in a liver biopsy specimen.

Hepatocellular carcinoma – a malignant liver tumor, representing one of the possible adverse outcomes of chronic hepatitis C, typically developing against the background of established liver cirrhosis.

Coinfection – infection with two or more infectious agents. In the context of chronic hepatitis C, it usually refers to concurrent infection with hepatitis B, D, and HIV viruses.

Pangenotypic – a characteristic of a drug or group of drugs effective against all major prevalent genotypes of the hepatitis C virus.

Sustained virological response (SVR) – the absence of hepatitis C virus RNA in the blood at 12 weeks post-treatment.

Liver fibrosis – the process of replacing liver parenchymal tissue with connective tissue, representing a universal tissue response to chronic injury.

Liver cirrhosis – the terminal stage of chronic liver disease, characterized by the replacement of parenchyma with connective tissue and distortion of the organ architecture. In early stages with preserved liver function, it is termed compensated; when function is lost, it is termed decompensated.

APRI – a non-commercial calculated liver fibrosis index, a non-invasive diagnostic method. It can be used as an alternative when liver elastography is unavailable.

FIB-4 – a non-commercial calculated liver fibrosis index, a non-invasive diagnostic method. It can be used as an alternative when liver elastography is unavailable.

METAVIR – a popular scoring system for assessing the grade of inflammation (from A0 to A3) and stage of fibrosis (from F0 to F4) in liver tissue. It is used both for characterizing liver biopsy specimens and for assessing liver fibrosis using non-invasive methods (e.g., liver elastography or fibrosis index calculation) (see Appendix G).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic hepatitis C (CHC) – a chronic inflammatory disease lasting longer than 6 months with predominant involvement of liver tissue due to hepatitis C virus (HCV) infection, which can lead to severe consequences such as cirrhosis, liver cancer (hepatocellular carcinoma, HCC), and death [1].

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

The causative agent of CHC is HCV, which is a small hepatotropic RNA virus belonging to the Flaviviridae family. The virus consists of a nucleocapsid containing the core protein (HCVcAg) and single-stranded (+) RNA, and an envelope containing human apolipoprotein E (apoE) and viral proteins E1 and E2. The viral genome encodes 10 different proteins, including the 3 structural proteins mentioned above and 7 non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) [2].

There are 8 genotypes (GT) [3], designated by Arabic numerals from 1 to 8, and several dozen subtypes of HCV, designated by Latin letters. Subtypes of GT 1 (a and b) are of the greatest clinical significance. Genotypes and subtypes differ in sequences by approximately 30% and 20%, respectively. The variability of the viral genome causes structural changes in antigenic determinants that dictate the production of specific antibodies. This hinders viral clearance from the body and the development of an effective vaccine against HCV [4,5].

HCV infection in the majority of cases (55-85%) leads to a chronic disease course and in approximately a quarter of patients results in the development of LC over the subsequent decades, which in turn can serve as a basis for the formation of HCC [6]. Quite frequently, due to the predominantly asymptomatic nature of the infection, the disease first manifests with complications of LC.

The leading pathogenetic mechanism in CHC is impaired interaction between immune cells and HCV-infected hepatocytes. Liver tissue damage is primarily the result of the immune response mounting within the inflammatory focus rather than the cytopathic effect of the virus [7]. Immunocompetent cells accumulate in the liver, some of which (NK cells, cytotoxic T lymphocytes) exhibit high cytotoxicity and the ability to damage hepatocytes [8]. Contact between infected hepatocytes and CTLs (a component of the adaptive immune response) triggers apoptosis. There is a deficit in the T-cell system, macrophage depression, impaired interferonogenesis, and an absence of specific antibody production against viral antigens, which ultimately disrupts the immune system's adequate recognition and clearance of viral antigens on the surface of hepatocytes [8-11].

Patients with a pronounced T-cell response achieve complete HCV clearance following acute hepatitis C. As a result of the interaction between the virus and the immune system, the activity of CTLs is suppressed by viral proteins. Consequently, immunological tolerance to the virus develops in CHC [12].

The action of the virus in CHC and the immunological reactions it triggers cause damage not only to the liver but also to other organs and tissues. The concept of systemic manifestations in CHC involves the potential for extrahepatic viral replication, specifically in lymphoid and non-lymphoid tissues [13]. Viral replication in immunocompetent cells (lymphocytes) leads to impaired immunological function. The persistence of HCV in monocytes is the main cause of reinfection after liver transplantation in patients with severe CHC [10].

Host factors influencing the outcome and course of CHC include age at infection, alcohol abuse, coinfection with hepatotropic viruses, lipid metabolism disorders, etc. [14,15].

1.3 Epidemiology of the Disease or Condition

According to estimates, 1% of the global population (about 71 million people) tests positive for anti-HCV antibodies, of whom two-thirds are chronically infected and one-third have recovered spontaneously or through treatment. The disease is more prevalent in Africa and Asia (nearly 3% of the population), whereas in the Americas and Europe it is detected in 1.5-2.0% [17]. The exact prevalence of CHC in the Russian Federation remains unknown, with the estimated number of patients reaching up to 4.9 million [16]. According to Rospotrebnadzor, as of January 1, 2017, there were 591,830 CHC patients under dispensary observation across the regions of the Russian Federation [16].

In Russia, the most prevalent genotypes are GT 1 (52.6%, of which 3.7% belong to subtype 1a and 48.9% to subtype 1b) and GT 3 (39.6%), whereas GT 2 is much less common (7.8%). Genotypes 4–6 account for less than 0.01% of cases, while GT 7 and 8 are extremely rare [16]. With the advent of pangenotypic direct-acting antiviral regimens for chronic hepatitis C (CHC), the clinical significance of HCV genotypes is gradually diminishing, though a number of genotype-specific regimens remain for which determination of the HCV genotype is required prior to initiation.

The source of infection is an infected human. The most significant route of transmission is parenteral (via intravenous drug use, medical procedures, traumatic cosmetic procedures including manicures and pedicures, tattooing, and body piercing), while sexual and vertical transmission routes are significantly less common [18].

The risk of occupational transmission for healthcare workers following an accidental needle-stick injury with blood-contaminated with the virus is approximately 1.8%. If a patient's blood contacts damaged skin or intact mucous membranes of a healthcare worker, the risk of infection is considerably lower, whereas contact with intact skin poses no risk. Consequently, the overall risk of infection for medical personnel is low. The risk of transmitting the infection from an infected healthcare worker to a patient is extremely low [18]. The risk of perinatal transmission is 5–10% and shows little correlation with the mode of delivery, though it increases to 14–16% in the presence of maternal HIV coinfection [18]. The low concentration of the virus in sex gland secretions and organs accounts for the low risk of sexual transmission: approximately 0.5% per year for unprotected sexual intercourse in a monogamous heterosexual couple, approximately 0.4–1.8% per year among commercial sex workers [19], and approximately 0.8% per year among men who have sex with men with HCV monoinfection (which is 4 times higher in the presence of HIV coinfection) [20].

HCV exhibits relatively low resistance to environmental factors. The virus is known to be stable at temperatures up to 50°C; complete inactivation occurs within 30 minutes at 60°C and within 2 minutes at 100°C. The virus is sensitive to ultraviolet radiation and lipid solvents [21].

1.4 Features of Coding the Disease or Condition

B18.2 – Chronic viral hepatitis C.

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

1.5 Classification of the disease or condition

The disease is classified according to the HCV genotype, as well as the presence of cirrhosis and extrahepatic manifestations.

By stage:

0 – no fibrosis;

1 – mild fibrosis;

2 – moderate fibrosis;

3 – advanced fibrosis;

4 – severe fibrosis (cirrhosis).

By HCV genotype:

1. – genotype 1

   • Genotype 1a

   • Genotype 1b

2. – genotype 2 (including 2k1b)

3. – genotype 3

4. – genotype 4

5. – genotype 5

6. – genotype 6

7. – genotype 7

8. – genotype 8

1.6 Clinical presentation of the disease or condition

In most patients, the disease is asymptomatic and is detected during routine health check-ups (dispensary screening), pre-hospital evaluation, visits to a gastroenterologist for dyspeptic symptoms (typically not directly related to the presence of CHC), or consultations with other specialists (gynecologists, urologists, dentists, etc.). Several years may elapse between the time of infection and diagnosis. In some cases, the initial presentation of the disease consists of B-cell lymphoproliferative or immune-mediated extrahepatic disorders (cryoglobulinemic vasculitis, including Raynaud's syndrome; interstitial lung disease; glomerulonephritis; Sjögren's syndrome; arthritis, etc.). In a substantial number of patients, the diagnosis is established only after the onset of complications of cirrhosis, such as esophageal and gastric variceal bleeding or ascites development [22,23].

Physical examination generally reveals no pathological findings in the absence of cirrhosis [22].

Transaminase activity can be either elevated or within reference ranges. In some cases, periodic elevations in ALT activity are observed. Anti-HCV and HCV RNA are detected in the blood. ALT activity within normal limits does not indicate the absence of liver changes, and patients cannot be considered "healthy carriers". It has been shown that cirrhosis can be diagnosed in 30-50% of such patients [24,25]. Often, in the early stage of compensated cirrhosis, only weight loss, asthenia, and decreased performance are noted. Physical examination reveals hepatomegaly with a firm liver consistency and splenomegaly. However, in 20% of patients, early-stage cirrhosis is asymptomatic and is usually discovered incidentally during a routine check-up or examination for another disease.

Liver cirrhosis develops, as a rule, in 25-35% of chronic hepatitis C cases. The probability of its development is 7.3% per year (5.1-9.5%). In many patients, cirrhosis as an outcome of chronic hepatitis C is first diagnosed based on liver biopsy histological data. The rate of cirrhosis decompensation is 5.5% per year. The probability of developing portal hypertension syndrome within a year in patients with compensated cirrhosis is 3.6%, hepatic encephalopathy is 0.4%, and HCC is 1.5% [24,26,27].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for chronic hepatitis C:

The diagnosis of chronic hepatitis C is established based on the presence of antibodies to the hepatitis C virus (determination of total class M and G antibodies [anti-HCV IgG and anti-HCV IgM] to hepatitis C virus in the blood, hereinafter referred to as anti-HCV) and hepatitis C virus RNA (determination of hepatitis C virus RNA in the blood by PCR, qualitative assay, hereinafter referred to as HCV RNA) or HCV core antigen (determination of hepatitis C virus core antigen in the blood, hereinafter referred to as HCVcAg) for more than 6 months [1].

2.1 Complaints and Anamnesis

There are no specific symptoms characteristic of chronic hepatitis C. The disease is usually asymptomatic and quite often manifests with complications of cirrhosis (ascites, esophageal and gastric variceal bleeding, hepatic encephalopathy) [28]. In some cases, immunologically mediated extrahepatic manifestations are the first signs of the disease [23].

2.2 Physical Examination

Physical examination generally reveals no abnormalities. Signs of cirrhosis may be present (ascites, palmar erythema, abdominal wall varices, edema, splenomegaly). When immunologically mediated extrahepatic manifestations develop, corresponding changes are present [23].

2.3 Laboratory Diagnostics

At the screening stage

Screening for chronic hepatitis C is based on the detection of anti-HCV. If anti-HCV are detected, testing for HCV RNA must be performed. If HCV RNA testing is unavailable, testing for HCVcAg is acceptable. This antigen in blood serum or plasma is also a marker of HCV replication. The HCVcAg assay is less sensitive than HCV RNA (the lower limit of detection is equivalent to approximately 500-3000 IU/mL of HCV RNA, depending on the HCV genotype [28,29]). In rare cases, HCVcAg is not detected in the presence of detectable HCV RNA [30].

Comments: belonging to a high-risk group is generally determined based on the patient's history (occupation, history of transfusion, injection drug use, sexual partners, family history, etc.).

High-risk groups include:

• Pregnant women;

• Recipients of blood and blood components, organs, and tissues;

• Medical organization personnel;

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

• Patients of addiction treatment and dermatovenereology clinics;

• Wards and staff of round-the-clock child or adult care facilities;

• Contacts in foci of acute and chronic hepatitis C;

• Injection drug users and their sexual partners;

• Sex workers and their sexual partners;

• Men who have sex with men;

• Individuals with a high number of casual sexual partners;

• Individuals who have received tattoos;

• Inmates in correctional facilities;

• Donors of blood (its components), organs and tissues, and sperm;

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

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

Sanitary rules (SanPiN 3.3686-21, Appendix 18) define population groups subject to mandatory simultaneous screening for anti-HCV and HCV RNA [234]: (see Appendix A3 Table 1)

• All patients with detected antibodies to hepatitis C virus (Hepatitis C virus) in the blood (anti-HCV) are recommended to undergo qualitative determination of hepatitis C virus (Hepatitis C virus) RNA in the blood by PCR, or determination of hepatitis C virus (Hepatitis C virus) Core antigen in the blood (HCVcAg) (if the former is unavailable) to confirm the presence of a current infection [1].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

• All patients with detected antibodies to hepatitis C virus (Hepatitis C virus) in the blood (anti-HCV) and negative hepatitis C virus (Hepatitis C virus) RNA in the blood by PCR (or a negative hepatitis C virus (Hepatitis C virus) Core antigen in the blood (HCVcAg) if the former is unavailable) are recommended to undergo repeat qualitative determination of hepatitis C virus (Hepatitis C virus) RNA in the blood by PCR at 12 and 24 weeks to confirm or rule out the presence of chronic hepatitis C (CHC) [1].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: the presence of anti-HCV combined with HCV RNA (or HCVcAg) is characteristic of both patients with CHC and patients with acute hepatitis C. The concentration of HCV RNA (or HCVcAg) in patients with acute hepatitis C can fluctuate significantly, down to undetectable levels. Thus, patients with undetectable HCV RNA (or HCVcAg) need to be retested for HCV RNA (or HCVcAg) 12 and 24 weeks after the negative result to verify HCV clearance (spontaneous recovery from acute hepatitis C) or confirm the development of CHC.

At the diagnostic stage:

• Determination of hepatitis C virus genotype (determination of hepatitis C virus (Hepatitis C virus) genotype, hereinafter referred to as HCV GT) is recommended only for patients with CHC to plan a genotype-specific antiviral therapy (AVT) regimen [1].

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

Comments: HCV GT is relevant only when planning genotype-specific antiviral drugs. With the availability of pangenotypic drugs, this testing is not required.

• All patients with CHC progressing to cirrhosis and/or presenting with extrahepatic manifestations (lymphoproliferative disorders) are recommended to undergo a complete blood count (CBC) [23,36-38].

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

Comments: the course of CHC may affect the cellular composition of the blood, but there is no compelling evidence of such changes in the absence of cirrhosis and HCV-induced lymphoproliferative disorders. When cirrhosis develops, varying degrees of thrombocytopenia are most commonly observed, and less frequently, other types of cytopenia.

• All patients with CHC are recommended to undergo a general biochemical blood test (determination of alanine aminotransferase and aspartate aminotransferase activity, total bilirubin level, and blood creatinine level) to assess the severity of hepatocyte damage, as well as liver and kidney function [39-41].

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

Comments: in the absence of signs of cirrhosis, the clinical significance of transaminase activity and other liver function parameters (bilirubin, albumin) is small. It becomes more significant if there is concomitant liver pathology. In patients with cirrhosis resulting from CHC, the severity of hepatocyte damage and signs of decompensation are crucial in choosing patient management tactics, AVT drugs, and predicting disease progression [39]. In addition, ALT and AST can be used for independent assessment of the severity of liver fibrosis (e.g., APRI, FIB-4 indices) when instrumental examination is not feasible [42] (see Appendix G). Assessment of renal function (blood creatinine testing) is necessary when planning AVT regimens containing sofosbuvir** [40,41].

• All patients with CHC progressing to cirrhosis are recommended to have prothrombin (thromboplastin) time determined in blood or plasma to assess liver function [46].

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

Comments: 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%.

Comments: Chronic HCV infection is associated with a high risk of developing mixed cryoglobulinemia syndrome. [231,232] All patients with CHC and clinical manifestations of mixed cryoglobulinemia syndrome require prompt initiation of AVT [233]

At the antiviral therapy (AVT) stage:

• Laboratory monitoring is not recommended for patients with CHC without cirrhosis during AVT without the use of #ribavirin** [205,206].

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

Comment: modern DAA regimens have high safety and efficacy; therefore, routine laboratory monitoring during DAA therapy without the use of #ribavirin** is unnecessary.

• When using #RBV**, it is recommended to perform a complete blood count (CBC) every 2–4 weeks to rule out anemia, a common adverse effect of the drug [117].

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

Comment: there is no correlation between the rate of HCV elimination during antiviral therapy and the likelihood of sustained virological response (SVR); therefore, routine HCV RNA monitoring during treatment is unnecessary [48].

2.4 Instrumental Diagnostics

At the diagnostic stage:

• All patients with chronic hepatitis C are recommended to undergo a comprehensive ultrasound examination of the abdominal organs and retroperitoneal space to detect signs of cirrhosis and hepatocellular carcinoma (HCC) [52, 53].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Comprehensive ultrasound of the abdominal organs and retroperitoneal space is performed to diagnose HCC, signs of portal hypertension (splenomegaly, dilation of the portal system veins), ascites, and to rule out concomitant gastrointestinal pathology, which in some cases can be crucial for determining the disease stage and treatment tactics. Cirrhosis and HCC resulting from chronic hepatitis C can be asymptomatic and detected solely by ultrasound. If a liver lesion suspicious for HCC is detected, further evaluation should be pursued in accordance with clinical guidelines for the diagnosis and treatment of HCC.

• All patients with chronic hepatitis C are recommended to undergo non-invasive fibrosis assessment to determine antiviral treatment tactics and further patient management (in cases of cirrhosis) [54–58].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: non-invasive diagnostics allow for highly accurate determination of the fibrosis stage. This can be performed using transient elastography (on a validated device) or serum biomarker panels. If elastography is unavailable, non-commercial calculated indices based on laboratory test results may be used (e.g., APRI, FIB-4 indices, see Appendices G).

• In case of discordant non-invasive diagnostic results, it is recommended to consider percutaneous liver biopsy to determine antiviral treatment tactics and further patient management (in cases of cirrhosis) [1].

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

Comments: Liver biopsy is an invasive procedure associated with the risk of complications and should therefore be performed only when results cannot be obtained using non-invasive methods [1].

Comments: Endoscopic examination is performed to diagnose the grade of esophageal and gastric varices, as well as for clipping or band ligation during bleeding or for the prevention of esophageal variceal bleeding in patients with cirrhosis. The procedure may be performed under sedation, which requires prior consultation and support from an anesthesiologist.

• Computed tomography (CT) of the abdominal organs with intravenous bolus contrast enhancement or magnetic resonance imaging (MRI) of the abdominal organs with intravenous contrast enhancement is recommended for patients with chronic hepatitis C if a liver lesion is detected on comprehensive abdominal ultrasound, in order to clarify its nature [62–65].

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

2.5 Other Procedures

Not applicable.

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

The goal of chronic hepatitis C treatment is the eradication of HCV to prevent complications of chronic hepatitis C (including cirrhosis, HCC, death), improve quality of life, and prevent further transmission of HCV in the population. Hepatitis C virus does not form highly stable intracellular forms of genetic material and can therefore be completely eradicated from the body [1]. The indicator of viral eradication from the body is the sustained achievement of undetectable blood viral RNA levels, assessed 12 weeks after the end of therapy (SVR12) [29, 30].

The choice of treatment regimen is influenced by the following factors [68]:

• liver fibrosis stage, presence of cirrhosis, and its class;

• HCV genotype;

• presence of certain comorbid conditions;

• history of prior antiviral therapy (if any);

• concurrent medications taken for comorbid conditions.

3.1 Indications for initiation of antiviral therapy

• Antiviral treatment is recommended for all patients with chronic hepatitis C, regardless of the presence of cirrhosis, in order to achieve cure (HCV eradication) [1,69] (see also Appendix A3).

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Treatment of chronic hepatitis C is indicated for all patients, as highly effective and safe drugs are currently available that allow achieving SVR in the vast majority of cases.

• Prompt consideration of therapy is recommended primarily in patients:

  • with chronic hepatitis C progressing to cirrhosis (including decompensated cirrhosis);

  • with advanced fibrosis (F3 according to METAVIR);

  • with clinically significant extrahepatic manifestations;

  • with HCV recurrence after liver transplantation;

  • at risk of rapid progression of liver disease due to comorbidities (chronic viral hepatitis B, HIV infection, diabetes mellitus, etc., after non-liver solid organ transplantation);

  • women of childbearing potential wishing to become pregnant;

  • at high risk of transmission, including prison inmates, individuals with high-risk sexual behavior, people who inject drugs, etc. [1,69].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• Before prescribing DAAs, it is recommended to check for potential drug-drug interactions between the prescribed regimen and the patient's current medications using any specialized resource (e.g., https://www.hep-druginteractions.org). If a significant interaction is identified, it is recommended to substitute the regimen or the concomitant medication used to treat the comorbid condition. If this is not possible, decisions should be made on an individual basis by assessing the risk-benefit ratio of the combination and the potential consequences of its use [70].

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

Comments: Most DAAs are safe, but their pharmacokinetic properties may lead to significant interactions with other medications taken by the patient.

3.2 Treatment of patients without liver cirrhosis and with compensated liver cirrhosis

• Treatment of chronic hepatitis C patients without cirrhosis, without prior antiviral therapy, and without a history of liver transplantation is recommended using one of the alternative regimens according to Table 2 of Appendix A3

• - Glecaprevir + pibrentasvir** [85]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• - Velpatasvir + sofosbuvir** [76,79]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• - Daclatasvir** + sofosbuvir** [105,107,208,218-220]

Level of Evidence AGrade of Evidence 3Level of Recommendations A (Grade of Evidence – 3)

• - Grazoprevir + elbasvir** or grazoprevir + elbasvir** + #ribavirin** (GZR+EBV** 100/50 mg 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg. Treatment course 16 weeks) or grazoprevir + elbasvir** + sofosbuvir** for genotype 3 [93,207, 221-224, 237-240, 244]

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

• - Daclatasvir** + narlaprevir** + #ritonavir** (DCV** 60 mg once daily + NRV** 200 mg once daily (2 tabs simultaneously, 100 mg each) + #r** 100 mg once daily. Treatment course 12 weeks) [109]

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

• - Ledipasvir + sofosbuvir [90, 225]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Narlaprevir** + sofosbuvir** + #ritonavir** (NRV** 200 mg once daily (2 tabs simultaneously, 100 mg each) + #r** 100 mg once daily + SOF** 400 mg 1 tab. once daily. Treatment course 12 weeks; in patients with mild fibrosis (F0-2) and viral load <1,000,000 IU/mL, an 8-week duration may be considered by decision of the medical commission) [110,209]

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

• Treatment of chronic hepatitis C patients with compensated cirrhosis without prior antiviral therapy is recommended using one of the alternative regimens according to Table 3 of Appendix A3

• - Velpatasvir + sofosbuvir** or velpatasvir + sofosbuvir** + #ribavirin** (VEL+SOF** (100/400 mg) 1 tab. once daily + #RBV** 400-1000 mg/day for weight <75 kg, 1200 mg/day for ≥75 kg; in Child-Pugh B/C start at 600 mg/day. Treatment course 12 weeks) [76, 79, 237, 245, 254, 260]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Glecaprevir + pibrentasvir** [83-85,229]

Level of Evidence AGrade of Recommendation 4Level of Clinical Evidence A (level of evidence validity – 4)

• - Daclatasvir** + sofosbuvir** for genotypes 1, 2, and 4 [106,107,218]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Daclatasvir** + sofosbuvir** + #ribavirin** (DCV** 60 mg 1 tab. once daily + SOF** 400 mg 1 tab. once daily + #RBV** RBV 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course 24 weeks) [237, 246, 247, 254, 263-266]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Grazoprevir + elbasvir** or grazoprevir + elbasvir** + #ribavirin** (GZR+EBV** 100/50 mg 1 tab. once daily + #RBV** 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course 16 weeks) [93,207, 223, 226, 237, 254, 255]

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

• - Grazoprevir + elbasvir** + sofosbuvir** + #ribavirin** for genotype 3 (GZR+EBV** 100/50 mg 1 tab. once daily + #RBV** 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more + SOF** 400 mg 1 tab. once daily. Treatment course 12 weeks) [93,207, 223, 226, 237, 254, 256, 257]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• - Ledipasvir + sofosbuvir or ledipasvir + sofosbuvir + #ribavirin** (LDV+SOF 90/400 mg 1 tab. once daily + #RBV** 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course for genotypes 1 and 4 is 12 weeks, for genotype 3 is 24 weeks) [89-92,213- 217, 248, 254, 260, 261]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• Treatment of chronic hepatitis C patients who failed prior therapy with PegIFN** + #RBV** ± SOF** or SOF** + #RBV** without cirrhosis is recommended using one of the alternative regimens according to Table 4 of Appendix A3

• - Velpatasvir + sofosbuvir** [76, 79]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Glecaprevir + pibrentasvir** [83-85]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Daclatasvir** + sofosbuvir** or daclatasvir** + sofosbuvir** + #ribavirin** (DCV** 60 mg 1 tab. once daily + SOF** 400 mg 1 tab. once daily + #RBV 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course 12 weeks) [106,107,210,211,218, 237,249,250, 254, 263-266]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Grazoprevir + elbasvir** or grazoprevir + elbasvir + #ribavirin** (GZR+EBV** 100/50 mg 1 tab. once daily + #RBV** 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course 16 weeks) [93,207, 223, 226, 237, 254, 255]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• - Ledipasvir + sofosbuvir or ledipasvir + sofosbuvir + #ribavirin** (LDV+SOF 90/400 mg 1 tab. once daily + #RBV** 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course 24 weeks) [89-92,213- 217, 251, 252, 254, 261, 262]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• Treatment of chronic hepatitis C patients who failed prior therapy with PegIFN** + #RBV** ± SOF** or SOF** + #RBV** with compensated cirrhosis is recommended using one of the alternative regimens according to Table 5 of Appendix A3

• - Velpatasvir + sofosbuvir** [76, 79]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• - Glecaprevir + pibrentasvir** [84,85]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Daclatasvir** + sofosbuvir** [106,107, 218, 227]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

• - Daclatasvir** + sofosbuvir** + #ribavirin** (DCV** 60 mg 1 tab. once daily + SOF** 400 mg 1 tab. once daily + #RBV** 1000 mg/day for body weight <75 kg and 1200 mg/day for body weight ≥75 kg. Treatment course 24 weeks) [108,210,211, 218, 237, 253, 254]

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

• - Grazoprevir + elbasvir** [93,207,223,226]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• - Grazoprevir + elbasvir** + #ribavirin** (GZR+EBV** 100/50 mg 1 tab. once daily + #RBV** 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course 16 weeks) [93,207,223,226, 237, 244, 254, 258, 259]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• - Ledipasvir + sofosbuvir or ledipasvir + sofosbuvir + #ribavirin** (LDV+SOF 90/400 mg 1 tab. once daily + #RBV** 1000 mg for weight under 75 kg or 1200 mg for weight 75 kg or more. Treatment course for genotype 1 and 4 is 12 weeks, for genotype 3 is 24 weeks) [90-92,213- 217, 251, 252, 254, 261, 262]

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

All the above-mentioned drugs for the treatment of chronic hepatitis C patients (all HCV genotypes) with cirrhosis (including decompensated) or without it, with or without prior antiviral therapy history, are summarized in Table 6 of Appendix A3

Treatment of patients with decompensated cirrhosis is described in sections 3.11 and 3.12.

Principles of re-treatment after an unsuccessful course of DAAs (inhibiting NS3/4A and/or NS5A) are discussed in section 3.4.

3.3 Monitoring of therapy

• All patients who have received chronic hepatitis C antiviral therapy are recommended to undergo qualitative HCV RNA testing 12 weeks post-treatment to assess the efficacy of the therapy. It is recommended to use highly sensitive assays (≤15 IU/mL) [46-48,111]. Undetectable HCV RNA 12 weeks post-treatment indicates cure of chronic hepatitis C. Conversely, a positive HCV RNA result at this time point indicates treatment failure.

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

• When using RBV**, it is recommended to perform a complete blood count every 2-4 weeks; if hemoglobin drops by 10 g/L or more from baseline, reduce the drug dose by 200 mg/day, and if hemoglobin concentration falls below 85 g/L, discontinue RBV** therapy [112-117].

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

Comments: Most modern direct-acting antiviral (DAA) regimens for chronic hepatitis C (CHC) are well tolerated; however, in some cases it is necessary to add RBV** (for certain regimens, particularly in patients with cirrhosis), a drug whose main side effect is non-immune hemolysis. When using RBV**, a complete blood count (CBC) with differential should be monitored and therapy adjusted if necessary.

• Based on the decision of the attending physician, regardless of the care delivery setting, to monitor antiviral therapy for CHC (including assessment of efficacy and safety) in adult patients, it is recommended to consider the use of telemedicine technologies [228, 230].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

3.4 Retreatment

In most cases (95–100%), the use of DAAs leads to SVR, though in rare cases SVR is not achieved.

• In case of DAA treatment failure, it is recommended to use a regimen with alternative drugs, as well as a combination of three drugs with different mechanisms of action (an NS3/4A inhibitor + an NS5A inhibitor + an NS5B inhibitor) without RBV** or with the addition thereof. If testing for HCV resistance mutations to various DAAs is available, it is recommended to perform it for the rational selection of a new regimen [71-76, 167, 212].

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

3.5 Pathogenetic therapy

Pathogenetic therapy for CHC is non-specific; it is performed when necessary, taking into account the specific patient's disease course.

3.6 Symptomatic therapy

Symptomatic therapy for CHC is non-specific; it is performed when necessary, taking into account the specific patient's disease course.

3.7 Surgical treatment

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

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

• Endoscopic ligation or sclerotherapy of esophageal and gastric varices is recommended for patients with cirrhosis to prevent or stop bleeding [121-125].

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

3.8 Extrahepatic manifestations of chronic hepatitis C

• Patients with extrahepatic immunologically mediated manifestations of CHC are recommended to be prescribed DAAs according to the regimens described above [23, 127-129].

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

Comments: CHC can manifest as extrahepatic immunologically mediated conditions (cryoglobulinemic vasculitis, including with Raynaud's syndrome, interstitial lung diseases, glomerulonephritis, Sjögren's syndrome, arthritis, etc.), as well as non-Hodgkin B-cell lymphomas. In all cases, DAAs should be prescribed according to the regimens described above. Early initiation of antiviral therapy significantly reduces the risk of extrahepatic manifestations.

3.9 Coinfection

3.9.1 HCV/HIV coinfection

Patients with CHC and HIV coinfection belong to a group requiring prompt antiviral therapy for CHC [1, 69]. The course of CHC in HIV-infected individuals depends on the severity of HIV-induced immunodeficiency. The probability of severe liver damage is particularly high when CD4+ T-lymphocyte counts drop below 200/µL. Liver-related progression is driven by an increase in viral load in the blood (2-fold to 8-fold) against the background of severe immunodeficiency. HIV and HCV coinfection leads to an increased rate of complications and associated mortality. Antiretroviral therapy in HCV/HIV-coinfected patients is associated with a potential risk of liver dysfunction due to its hepatotoxicity [130, 131].

• For the treatment of CHC in HIV-coinfected patients, it is recommended to use the same antiviral regimens as for HCV monoinfection, with the goal of HCV eradication [132-137].

ER CLE 4Level of recommendation confidence C (level of evidence – 4).

Comments: all DAA-based antiviral regimens require consideration of drug-drug interactions. One convenient way to assess drug interactions is to use the Liverpool HEP Drug Interactions Checker online resource (http://www.hep-druginteractions.org).

3.9.2 HCV/HBV coinfection

Patients with CHC and hepatitis B virus (HBV) coinfection belong to a group requiring prompt antiviral therapy for CHC [1, 69]. HCV/HBV coinfection accelerates disease progression and increases the risk of hepatocellular carcinoma (HCC) [138, 139].

• All CHC patients are recommended to be tested for past or current HBV infection: qualitative determination of hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies to hepatitis B core antigen (anti-HBc) in blood, and determination of antibodies to hepatitis B surface antigen (anti-HBs) in blood [140-143].

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

• Patients with HCV/HBV coinfection are recommended to be prescribed antiviral therapy with nucleosides and nucleotides (excluding reverse transcriptase inhibitors) to prevent HBV reactivation. Antiviral therapy with nucleosides and nucleotides (excluding reverse transcriptase inhibitors) is recommended for the entire duration of CHC therapy and for 12 weeks after its successful completion [142].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: since HCV typically suppresses HBV replication, eradication of the former virus may lead to reactivation of the latter. Therefore, during CHC treatment, markers of HBV activity should be carefully monitored, and if they increase, antiviral therapy for HBV infection should be prescribed. This therapy can also be prescribed prophylactically for the duration of CHC treatment and for 12 weeks thereafter upon its successful completion.

• Patients with CHC and anti-HBc (in the absence of HBsAg and anti-HBs) are recommended to undergo monthly blood alanine aminotransferase (ALT) testing during CHC antiviral therapy to rule out HBV reactivation [142].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

• In HCV/HBV coinfection, it is recommended to use the standard regimens described above for the treatment of CHC [1, 138, 142-145].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

3.10 Patients with chronic kidney disease

• For CHC antiviral therapy in patients with chronic kidney disease (CKD) (including severe CKD with eGFR <30 mL/min/1.73 m²), it is recommended to use DAAs in accordance with the general recommendations for CHC antiviral therapy in patients without CKD [146-155] (see subsection 3.2 and Appendix A3).

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: sufficient clinical experience has now been accumulated with the use of sofosbuvir** in patients with severe CKD [153-155], making it possible to prescribe sofosbuvir**-containing antiviral regimens to all such patients without dose adjustment of DAAs.

• For CHC antiviral therapy in patients with severe CKD (eGFR <30 mL/min/1.73 m²), it is nevertheless recommended to preferentially choose regimens not containing sofosbuvir**, where possible [146-152]:

  • Glecaprevir + pibrentasvir** for all HCV genotypes;

  • Grazoprevir + elbasvir** for genotypes 1 and 4;

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• In patients with decompensated LC (Child-Pugh class B or C) and severe CKD (with GFR <30 mL/min/1.73 m²) it is recommended to prescribe the following CHC antiviral therapy regimens for 24 weeks [153,154,156,157]:

• #Velpatasvir + sofosbuvir** (100/400 mg) 1 tab. once daily (for genotypes 1–6) [76, 77, 78, 79, 154, 247, 254]:

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

• Daclatasvir** 1 tab. (60 mg) once daily + sofosbuvir** 1 tab. (400 mg) once daily (for GT 1–4)

• Ledipasvir + sofosbuvir (for GT 1 and 4).

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

3.11 Patients with decompensated liver cirrhosis

• Treatment of patients with chronic hepatitis C (CHC) and decompensated liver cirrhosis (Child-Pugh class B or C) or a history of decompensation episodes is recommended using one of the alternative regimens (according to Table 7 of Appendix A3):

• - Velpatasvir + Sofosbuvir** (100/400 mg) 1 tab. once daily + #Ribavirin** (all GTs) 400–1000 mg/day for weight <75 kg, 1200 mg/day for ≥75 kg; for Child-Pugh B/C, start at 600 mg/day for 12 weeks [76, 78, 79, 254, 260];

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

• - Daclatasvir** 60 mg 1 tab. once daily + Sofosbuvir** 400 mg 1 tab. once daily + #Ribavirin** (for GT 1, 2, 3, 4) 1000 mg for weight <75 kg or 1200 mg for weight ≥75 kg for 12–24 weeks [105, 107, 208, 218–220, 254];

Level of Evidence AGrade of Evidence 3Level of Recommendations A (Grade of Evidence – 3)

• - Ledipasvir + Sofosbuvir (for GT 1, 4, 5, 6) for 24 weeks [89–92, 213–217, 251, 252, 254];

• - Ledipasvir + Sofosbuvir 90/400 mg 1 tab. once daily + #Ribavirin** (1000 mg for weight <75 kg or 1200 mg for weight ≥75 kg) (for GT 1, 4, 5, 6) for 12 weeks [89–92, 213–217, 251, 252, 254];

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

3.12 Liver transplantation

3.12.1 Antiviral therapy for CHC in patients with decompensated liver cirrhosis on the liver transplantation waiting list

The goals of CHC antiviral therapy in patients with decompensated liver cirrhosis on the orthotopic liver transplantation (OLT) waiting list are:

• Prevention of liver graft infection;

• Improvement of liver function prior to transplantation;

• Removal of the patient from the OLT waiting list.

Improvement in liver function is assessed by clinical parameters, as well as by the Child-Pugh (see Appendix G) and MELD scores (any online resource, such as https://www.mdcalc.com/meldna-meld-na-score-liver-cirrhosis, can be used to calculate this index). An improvement in the MELD score is observed in 60% of patients with decompensated cirrhosis who have completed a course of antiviral therapy. This improvement is more likely and more pronounced the lower the MELD score is prior to therapy initiation.

Up to 25–30% of patients with decompensated cirrhosis may experience sustained improvement (compensation) of cirrhosis, making it possible to remove them from the OLT waiting list. The 3-year survival rate of such patients is no lower than that of liver transplant recipients who underwent OLT and are comparable in baseline MELD score [118, 119, 158–162].

• Patients with decompensated cirrhosis due to CHC (Child-Pugh class B or C) without HCC who are awaiting OLT are recommended to receive antiviral therapy if MELD < 20. Antiviral therapy should be initiated as soon as possible to complete the course and evaluate the response prior to transplantation [165, 166].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: The use of NS3/4 protease inhibitor drugs is strictly contraindicated for antiviral therapy in patients with decompensated cirrhosis.

• Patients with decompensated cirrhosis due to CHC (Child-Pugh class B or C) without HCC who are awaiting liver transplantation and have a MELD score ≥ 20 are recommended to undergo OLT without initiating antiviral therapy. Antiviral therapy for CHC is recommended to be performed after transplantation [165, 166].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

• Patients with decompensated cirrhosis due to CHC (Child-Pugh class B or C) without HCC who are awaiting OLT and have a MELD score ≥ 20 may start treatment prior to OLT if the anticipated organ waiting time exceeds 6 months [165, 166].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

3.12.2 Antiviral therapy for hepatitis C virus infection in liver transplant recipients

• Antiviral therapy for HCV-induced graft infection is recommended for all recipients in whom HCV RNA is detected in the blood, as soon as the patient's condition permits [176, 177].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: The SVR rate in liver transplant recipients with compensated graft disease who completed the scheduled course of antiviral therapy is over 95%. SVR is associated with delayed fibrosis progression and improved graft and recipient survival.

3.12.3 Antiviral therapy for CHC in recipients of the liver and other solid organs from donors with antibodies to hepatitis C virus

Currently, organ transplantation from anti-HCV-positive donors is not permitted in the Russian Federation. International clinical guidelines address patient management in cases of solid organ transplantation from donors with HCV viremia [1, 46].

3.13 Pregnant women

Pregnancy does not appear to have a negative impact on the course of CHC. Serum ALT activity decreases during the first and third trimesters of pregnancy and increases postpartum. HCV RNA levels increase during the first and third trimesters, peaking in the third trimester, and decline after delivery. These fluctuations are likely due to the immunosuppressive effects of pregnancy and the expansion of maternal plasma volume [191, 192]. Mother-to-child transmission of HCV occurs with an overall frequency of 5% to 15% [193, 194]. There is no compelling evidence of a negative impact of HCV on fetal development and pregnancy outcomes. There are isolated reports regarding the effect of cirrhosis on the course and outcome of pregnancy. Thus, pregnant women with cirrhosis are at an increased risk of adverse maternal outcomes (e.g., preeclampsia, hemorrhagic complications, and death) and fetal outcomes (e.g., preterm birth, low birth weight, and neonatal death). Women with cirrhosis due to CHC should be informed of these potential complications [195, 196].

• Women of reproductive age are recommended to undergo CHC antiviral therapy prior to planning a pregnancy to reduce the risk of HCV transmission to the future child [197].

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

• To detect CHC, pregnant women are recommended to be screened for anti-HCV in the blood (determination of total IgM and IgG classes of antibodies (anti-HCV IgG and anti-HCV IgM) to Hepatitis C virus in the blood) during the first trimester (upon registration for pregnancy) and the third trimester of pregnancy [198].

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

Comments: To date, there are no large-scale clinical trials evaluating the safety of DAAs during pregnancy. Dedicated studies of antiviral therapy with SOF** and LED+SOF during pregnancy have demonstrated good fetal safety. Currently, there are no data on the use of pangenotypic regimens during pregnancy.

• Women of childbearing potential receiving CHC antiviral therapy containing ribavirin** are not recommended to become pregnant during antiviral therapy and for at least 6 months after its discontinuation [201, 202].

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

• Men receiving CHC antiviral therapy containing ribavirin** are not recommended to father children with their female partners during antiviral therapy and for at least 6 months after its discontinuation [201, 202].

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

Comments: Ribavirin** has teratogenic properties, meaning it can cause developmental abnormalities and fetal death. It should not be prescribed to pregnant women or women of childbearing potential who may become pregnant during treatment with ribavirin** or within 6 months after stopping ribavirin**. In addition, it should be borne in mind that ribavirin** can similarly cause birth defects in the fetus if a man received ribavirin** while a woman conceived a child from him. Therefore, to avoid pregnancy during ribavirin** treatment and for at least 6 months thereafter, individuals of reproductive potential must use at least 2 forms of effective contraception. The consulting physician must document the discussion of the potential teratogenic effects of ribavirin** in the patient's medical record.

• Women with CHC are not recommended to discontinue breastfeeding, except in cases of nipple trauma and bleeding from these lesions [203, 204].

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

Comments: Breastfeeding does not pose a risk for mother-to-child HCV transmission, as the rate of infection in children, according to studies, is comparable between breastfed and formula-fed groups. However, in the event of nipple trauma and bleeding from these lesions, there is a risk of the child contracting the infection from an HCV-infected mother due to blood-borne HCV transmission.

3.14 Patients with concomitant oncological diseases

It is known that cancer treatment can negatively affect liver function in patients with HCV infection. Antiviral therapy may help create more favorable conditions for initiating or continuing chemotherapy by reducing the risk of liver disease progression [235].

• Patients with HCV and comorbid oncological diseases may also be recommended antiviral treatment using DAAs in accordance with general guidelines, including in combination (concurrently) with specific chemotherapy, taking into account potential drug-drug interactions [236].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

No specialized rehabilitation measures have been developed for patients with CHC.

5. Prevention and Dispensary Observation

5.1 Specific prevention

Specific prophylaxis for CHC has not been developed to date.

• Patients with CHC are recommended vaccination against hepatitis A and B to prevent infection with these viruses [1, 183–186].

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

5.2 Nonspecific prevention

5.3 Dispensary follow-up

• For patients with chronic hepatitis C (CHC) in whom AVT is postponed, it is recommended to conduct follow-up monitoring (dispensary observation) once a year with a comprehensive clinical, laboratory, and instrumental examination for dynamic monitoring [54, 55, 57, 59-61, 66, 67] (see also subsections 2.3, 2.4):

  • For all patients with CHC: general clinical blood biochemistry, comprehensive ultrasound of the abdominal organs and retroperitoneal space, liver elastometry (if unavailable, non-commercial calculated indices based on laboratory results may be used, such as APRI and FIB-4 index calculations (see Appendix G))

  • For all patients with CHC progressing to cirrhosis: complete blood count, prothrombin (thromboplastin) time in blood or plasma, esophagogastroduodenoscopy (EGD).

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

Comment: patients with anti-HCV who lack HCV RNA for 12 weeks after completing CHC AVT are considered cured of CHC and, in the absence of established risk factors for further progression of liver fibrosis, are subject to discontinuation of dispensary monitoring.

• After being cured of CHC, patients with cirrhosis or significant liver fibrosis (F3 by METAVIR) are recommended to undergo lifelong screening examinations for early detection of HCC (comprehensive ultrasound of the abdominal organs every 6 months) [53].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: these patients retain the risk of developing HCC despite the elimination of the virus from the body; therefore, they need preventive examinations for its early detection.

At the stage of dispensary follow-up:

Comment: after successful AVT, anti-HCV antibodies persist for a long time in the vast majority of cases; therefore, this test cannot be used to determine reinfection in patients with a history of HCV elimination. The proportion of patients in whom anti-HCV antibodies gradually disappear is very small, and the timeframe for this disappearance is unknown.

• All patients who have completed a course of CHC AVT are recommended to undergo HCV RNA testing 12 weeks after the end of AVT to evaluate its efficacy (SVR₁₂) [46-48] (see Appendix B).

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

Comment: the absence of HCV RNA 12 weeks after completing AVT corresponds to a cure for CHC, as late relapse occurs in less than 0.2% of cases [48].

• After cure of CHC, patients with cirrhosis or significant liver fibrosis (F3 by METAVIR) are recommended to undergo lifelong AFP level determination once every 6 months for the diagnosis of HCC [44, 45].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comment: the risk of developing HCC at the cirrhosis stage is about 1-5% per year. The probability of death within the first year after diagnosis in patients with HCC is 33%.

6. Organization of Medical Care

Medical care is provided in the following forms:

• emergency medical care;

• urgent medical care;

• planned medical care.

6.1 Conditions for the provision of medical services

Medical care is provided in the form of:

• primary health care;

• emergency medical care, including specialized emergency medical care;

• specialized medical care, including high-tech medical care.

Medical care for adult patients with CHC can be provided in the following settings:

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

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

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

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

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

Primary physician-delivered health care is provided by a district general practitioner or general practitioner (family doctor) on an outpatient basis.

Primary specialized health care is provided by an infectious disease specialist or gastroenterologist of a medical organization providing outpatient care to patients.

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

Treatment of patients is carried out in a round-the-clock or day hospital setting upon referral by a district general practitioner, general practitioner (family doctor), infectious disease specialist, gastroenterologist, or medical personnel who detected CHC.

Patients with CHC must be monitored until achieving SVR12, and in the presence of F3-4 liver fibrosis by METAVIR, for life.

The indication for emergency hospitalization is the development of acute liver failure, including hepatic encephalopathy and acute-on-chronic liver failure.

Medical care for patients with CHC is provided in accordance with the approved standard of specialized medical care.

7. Additional Information

None.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Bogomolov, Pavel Olegovich – PhD in Medical Sciences, Head of the Hepatology Department, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky.

2. Volchkova, Elena Vasilyevna – MD, Professor, Head of the Department of Infectious Diseases, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

3. Gusev, Denis Alexandrovich – MD, Professor, Chief Physician of the Clinical Infectious Diseases Hospital named after S.P. Botkin, Head of the Department of Infectious Diseases, Institute of Medical Education, Almazov National Medical Research Centre.

4. Dmitriev, Alexander Sergeevich – PhD in Medical Sciences, Head of the Center for Epidemically Significant Infectious Diseases, National Medical Research Center of Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health, Infectious Diseases Physician.

5. Zharkova, Maria Sergeevna – PhD in Medical Sciences, Head of the Hepatology Department, Clinic of Propeudeutics of Internal Diseases, Gastroenterology and Hepatology named after V.Kh. Vasilenko, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

6. Zhdanov, Konstantin Valeryevich – MD, Professor, Corresponding Member of the Russian Academy of Sciences, Director of the Scientific and Clinical Center of the Federal Scientific and Clinical Center for Infectious Diseases of the Federal Medical-Biological Agency.

7. Ivashkin, Vladimir Trofimovich – MD, Professor, Academician of the Russian Academy of Sciences, President of the Russian Gastroenterological Association and the Russian Study of the Liver Association, Head of the Department of Propaedeutics 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.

8. Kozlov, Konstantin Vadimovich – MD, Head of the Department of Infectious Diseases (with a course of medical parasitology and tropical diseases), S.M. Kirov Military Medical Academy of the Russian Ministry of Defense.

9. Kravchenko, Irina Eduardovna – MD, Professor of the Department of Infectious Diseases, Kazan State Medical University of the Russian Ministry of Health.

10. Maevskaya, Marina Viktorovna – MD, Professor, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Consultant at the Therapeutic Department No. 3, Clinical Hospital No. 2.

11. Mamonova, Nina Alekseevna – Researcher at the Laboratory of Genetic Technologies and Translational Research, National Medical Research Center of Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health.

12. Maslennikov, Roman Vyacheslavovich – PhD in Medical Sciences, Assistant Professor at the Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

13. Mikhailov, Mikhail Ivanovich – Professor, Academician of the Russian Academy of Sciences, Chief Researcher at the Laboratory of Molecular Epidemiology of Viral Hepatitis, Central Research Institute of Epidemiology of Rospotrebnadzor.

14. Novak, Ksenia Egorovna – PhD in Medical Sciences, Associate Professor, Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health.

15. Nikitin, Igor Gennadievich – MD, Professor, Head of the Department of Hospital Therapy No. 2, Faculty of General Medicine, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

16. Syutkin, Vladimir Evgenievich – MD, Leading Researcher at the Liver Transplantation Department, Sklifosovsky Research Institute for Emergency Medicine of the Moscow Healthcare Department, Professor at the Department of Surgery with courses in Oncosurgery, Endoscopy, Surgical Pathology, Clinical Transplantology and Organ Donation, A.I. Burnazyan Federal Medical Biophysical Center of the Federal Medical-Biological Agency.

17. Tikhonov, Igor Nikolaevich – Assistant Professor at the Department of Propaedeutics, Gastroenterology and Hepatology, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Gastroenterologist at the Hepatology Department, Clinical Hospital No. 2.

18. Chulanov, Vladimir Petrovich – MD, Professor, Chief freelance Infectious Diseases Specialist of the Russian Ministry of Health, Deputy Director for Science and Innovative Development, National Medical Research Center of Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health.

19. Sheptulin, Arkady Alexandrovich – MD, Professor at the Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

20. Shirokova, Elena Nikolaevna – MD, Professor at the Department of Propaedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).

21. Esaulenko, Elena Vladimirovna – MD, Professor, Head of the Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health.

Appendix A2. Methodology for Developing Clinical Guidelines

The purpose of these guidelines is to provide practitioners with modern concepts of the etiology and pathogenesis of chronic hepatitis C (CHC), as well as to familiarize them with currently used algorithms for its diagnosis and treatment.

Target audience of these clinical guidelines:

1. Infectious diseases physicians;

2. Gastroenterologists;

3. General practitioners (family physicians);

4. General practitioners.

Table А1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table А2. Scale for assessing levels of evidence (LE) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table А3. Scale for assessing grades of recommendation (GR) for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines

The revision mechanism for clinical guidelines provides for their systematic updating 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 when there are justified additions and/or comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and 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 the Russian Federation No. 494 of August 9, 2005, "On the Procedure for the Use of Medicinal Products in Patients for Vital Indications".

5. Order of the Russian Ministry of Health No. 804n of October 13, 2017, "On Approval of the Nomenclature of Medical Services".

6. Order of the Russian Ministry of Health No. 205n of May 2, 2023, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers".

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

8. Order of the Ministry of Labor of the Russian Federation No. 374n of July 26, 2024, "On Approval of Classifications and Criteria Used in Medical and Social Assessment of Citizens by Federal Medical and Social Assessment Institutions".

9. Federal Law No. 52-FZ of March 30, 1999, "On the Sanitary and Epidemiological Welfare of the Population"

10. Order of the Chief State Sanitary Doctor of the Russian Federation No. 12 dated June 25, 2025 "On amendments to the sanitary rules and norms SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases", approved by the order of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021"

11. Order of the Ministry of Health of the Russian Federation No. 330 dated August 5, 2003 "On measures to improve medical nutrition in healthcare institutions of the Russian Federation".

12. Order of the Ministry of Health of the Russian Federation No. 395n dated June 21, 2013, "On approval of therapeutic nutrition standards".

13. 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 medical nutrition".

Examples of diagnosis formulation

Example 1

Past hepatitis C virus (HCV) infection: convalescence resulting from spontaneous recovery (HCV RNA negative as of [date], anti-HCV positive as of [date]) Discharged/not discharged from follow-up (select option) [date].

Example 2

Past hepatitis C virus (HCV) infection: convalescence resulting from antiviral therapy during the period [specify start and end dates of antiviral therapy], sustained virological response achieved (HCV RNA negative as of [date]), anti-HCV positive as of [date]) Discharged/not discharged from follow-up (select option) [date].

Target groups subject to mandatory simultaneous testing for anti-HCV and HCV RNA

Table 1

CHCV antiviral therapy regimens for treatment-naive patients without cirrhosis, by genotype (drugs are listed in alphabetical order).

Table 2.

Notes:

VEL+SOF** – velpatasvir+sofosbuvir** (100/400 mg) 1 tab. q.d. or;

GLE+PIB** – glecaprevir+pibrentasvir** (3 tabs. simultaneously, 100/40 mg each) q.d.;

DCV** + SOF** – daclatasvir** 60 mg 1 tab. q.d. + sofosbuvir** 400 mg 1 tab. q.d.;

GZR+EBR** – grazoprevir+elbasvir** 100/50 mg 1 tab. q.d. or GZR+EBR** 100/50 mg 1 tab. q.d. + #RBV**[93,207, 223, 226, 237, 244, 254];

DCV** + RTV** + #r** – daclatasvir** 60 mg q.d. + narlaprevir** 200 mg q.d. (2 tabs. simultaneously, 100 mg each) + #ritonavir** 100 mg q.d.;

LDV+SOF – ledipasvir+sofosbuvir 90/400 mg 1 tab. q.d.;

RTV** + #r** + SOF** – narlaprevir** 200 mg q.d. (2 tabs. simultaneously, 100 mg each) + #ritonavir** 100 mg q.d. + sofosbuvir** 400 mg 1 tab. q.d.;

Comments on all regimens:

a - for viral load not exceeding 800,000 IU/mL, treatment duration is 12 weeks; for HCV viral load >800,000 IU/mL and/or in the presence of NS5A polymorphisms, a 16-week course should be considered in combination with #RBV** (at a dose of 1000 mg for patients weighing <75 kg and 1200 mg for patients weighing ≥75 kg) [167];

b - in patients with mild fibrosis (F0-2) #8 weeks, with fibrosis F3-F4 according to METAVIR – 12 weeks.

c - in patients with mild fibrosis (F0-2) and viral load less than 1,000,000 IU/mL, a duration of 8 weeks may be considered by decision of the medical commission.

CHCV antiviral therapy regimens for treatment-naive patients with compensated cirrhosis, by genotype (drugs are listed in alphabetical order).

Table 3.

Notes:

VEL+SOF** – velpatasvir+sofosbuvir** (100/400 mg) 1 tab. once daily or VEL+SOF** (100/400 mg) 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg [76,78,79, 237, 247, 254, 260] ;

GLE+PIB** – glecaprevir+pibrentasvir** (3 tabs. simultaneously, 100/40 mg each) once daily [85];

DAC**+SOF** – daclatasvir** 60 mg 1 tab. once daily + sofosbuvir** 400 mg 1 tab. once daily or DAC**+SOF** daclatasvir** 60 mg 1 tab. once daily + sofosbuvir** 400 mg 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg [105,107,208,218-220, 237, 246, 247, 254];

GRA+ELB** – grazoprevir+elbasvir** 100/50 mg 1 tab. once daily or GRA+ELB** 100/50 mg 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg and GRA+ELB** 100/50 mg 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg + SOF** 400 mg 1 tab. once daily [93,207, 221-224, 237-240, 244, 254, 255]

LED+SOF – ledipasvir+sofosbuvir 90/400 mg 1 tab. once daily or LED+SOF 90/400 mg 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg [89-92,213- 217, 248, 254, 260, 261]

a - for viral load not exceeding 800,000 IU/mL, treatment duration is 12 weeks; a 16-week course combined with #RBV** should be considered for HCV viral load >800,000 IU/mL and/or in the presence of NS5A polymorphisms;

b - for GT 3, adding #RBV** may be considered;

c - in case other treatment regimens are unavailable.

CHC antiviral regimens for patients non-responding to prior therapy with PegIFN** + RBV** ± SOF** or SOF** + RBV**, without liver cirrhosis, by genotype (drugs are listed in alphabetical order).

Table 4.

Notes:

VEL+SOF** – velpatasvir+sofosbuvir** (100/400 mg) 1 tab. once daily;

GLE+PIB** – glecaprevir+pibrentasvir** (3 tabs. simultaneously, 100/40 mg each) q.d.;

DCV** + SOF** – daclatasvir** 60 mg 1 tab. q.d. + sofosbuvir** 400 mg 1 tab. q.d.;

DAC** 60 mg 1 tab. once daily + SOF** 400 mg 1 tab. once daily + #RBV 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg [106,107,210,211,218, 237,249,250, 254]

GRA+ELB** – grazoprevir+elbasvir** 100/50 mg 1 tab. once daily or GRA+ELB** 100/50 mg 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg [93,207, 223, 226, 237, 254, 255]

LED+SOF – ledipasvir+sofosbuvir 90/400 mg 1 tab. once daily or LED+SOF 100/50 mg 1 tab. once daily + #RBV** 1000 mg if body weight is less than 75 kg or 1200 mg if body weight is 75 kg or more. Treatment course 24 weeks [89-92,213- 217, 251, 252, 254, 261, 262]

Comments on all regimens:

a - for viral load not exceeding 800,000 IU/mL, treatment duration is 12 weeks; for HCV viral load >800,000 IU/mL and/or in the presence of NS5A polymorphisms, a 16-week course combined with #RBV** (at a dose of 1000 mg for patients weighing <75 kg and 1200 mg for patients weighing ≥75 kg) should be considered [167];;

CHC antiviral regimens for patients non-responding to prior therapy with PegIFN** + RBV** ± SOF** or SOF** + RBV**, with compensated liver cirrhosis by genotype (drugs are listed in alphabetical order).

Table 5

Notes:

VEL+SOF** – velpatasvir+sofosbuvir** (100/400 mg) 1 tab. once daily or VEL+SOF** (100/400 mg) 1 tab. once daily + #RBV** 1000 mg if body weight is less than 75 kg or 1200 mg if body weight is 75 kg or more [167];

GLE+PIB** – glecaprevir+pibrentasvir** (3 tabs. simultaneously, 100/40 mg each) once daily [85];

DAC** + SOF** – daclatasvir** 60 mg 1 tab. once daily + sofosbuvir** 400 mg 1 tab. once daily or DAC** 60 mg 1 tab. once daily + SOF** 400 mg 1 tab. once daily + #RBV** 1000 mg if body weight is less than 75 kg or 1200 mg if body weight is 75 kg or more [105,107,208,218-220];

GRA+ELB** – grazoprevir+elbasvir** 100/50 mg 1 tab. once daily or GRA+ELB** 100/50 mg 1 tab. once daily + #RBV** 1000 mg/day if body weight <75 kg and 1200 mg/day if body weight ≥75 kg [93,207,223,226, 237, 244, 254, 258, 259]

LED+SOF – ledipasvir+sofosbuvir 90/400 mg 1 tab. once daily or LED+SOF 90/400 mg 1 tab. once daily + #RBV**** 1000 mg if body weight is less than 75 kg or 1200 mg if body weight is 75 kg or more. Treatment course for genotypes 1 and 4 is 12 weeks, for genotype 3 is 24 weeks [90-92,213- 217, 251, 252, 254, 261, 262]

Comments:

a - for viral load not exceeding 800,000 IU/mL, treatment duration is 12 weeks; for HCV viral load >800,000 IU/mL and/or in the presence of NS5A polymorphisms, a 16-week course combined with #RBV** (1000 mg if body weight is less than 75 kg or 1200 mg if body weight is 75 kg or more) should be considered [167];

b - for GT 3, adding #RBV** may be considered;

Antiviral therapy regimens for chronic hepatitis C according to genotype, prior treatment experience, and presence of liver cirrhosis (drug names are listed in alphabetical order)

Table 6

DAA regimens for chronic HCV in patients with decompensated liver cirrhosis (Child-Pugh class B or C) or a history of decompensation episodes

Table 7

Notes:

VEL+SOF** + #RBV** – velpatasvir+sofosbuvir** (100/400 mg) 1 tab. q.d. + #ribavirin** 1000 mg for weight <75 kg or 1200 mg for weight ≥75 kg [76,78, 79, 247, 254]);

DCV** + SOF** + #RBV** – daclatasvir** 60 mg 1 tab. q.d. + sofosbuvir** 400 mg 1 tab. q.d. + #ribavirin** 1000 mg for weight <75 kg or 1200 mg for weight ≥75 kg for 12-24 weeks [105,107,208,218-220, 254];

LDV+SOF + #RBV** – ledipasvir+sofosbuvir 90/400 mg 1 tab. q.d. + #ribavirin** 1000 mg for weight <75 kg or 1200 mg for weight ≥75 kg (for GT 1, 4, 5, 6) - 12 weeks [89-92, 213-217, 251, 252, 254];

a - International clinical guidelines for hepatitis C allow for the use of the #VEL+SOF** velpatasvir+sofosbuvir** (100/400 mg) 1 tab. q.d. regimen for 24 weeks in case of RBV** intolerance, per the decision of the medical panel [1, 46, 76, 78, 79].

b - Duration of 12 weeks for patients with liver cirrhosis (Child-Pugh class A or B). For genotype 3, therapy may be extended to 24 weeks, with or without #RBV**. Duration of 24 weeks for patients with Child-Pugh class C liver cirrhosis. For patients with RBV** intolerance, DCV** + SOF** therapy without RBV** for 24 weeks may be considered.

Activity of NS5A inhibitors against common baseline HCV resistance-associated substitutions

Source: American Association for the Study of Liver Diseases (AASLD) and IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org/evaluate/resistance, accessed February 2025 [254].

Most common clinically significant resistance-associated substitutions (RAS) by genotype, DAA, and fold-change in susceptibility

Recommendations in the event of missed doses of pangenotypic DAA combinations

Source: American Association for the Study of Liver Diseases (AASLD) and IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org/evaluate/monitoring#incomplete-adherence, accessed February 2025 [254].

Recommendations in the event of missed SOF/VEL or GLE/PIB doses for treatment-naive patients with compensated liver disease

Appendix B. Physician Action Algorithms

Diagnosis and treatment of chronic hepatitis C

Appendix C. Patient Information

Dear patient! You have been diagnosed with hepatitis C. Modern medications can completely cure this disease. This will prevent complications such as liver cirrhosis and liver cancer. The disease is usually asymptomatic and is detected incidentally during routine examinations. However, this does not mean it should not be treated. The scope of therapy will be determined by your attending physician, who will also determine the necessary diagnostic tests and their schedule. You must not independently stop or substitute medications, even if you feel better or consider yourself healthy. If you have any 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

Russian title: Assessment of liver cirrhosis severity using the Child-Pugh score

Source: Durand F., Valla D. Assessment of the prognosis of cirrhosis: Child–Pugh versus MELD // Journal of Hepatology. – 2005. – Vol. 42. – No. 1. – P. S100-S107

Type: rating scale

Purpose: assessment of liver cirrhosis severity

Contents:

Key (interpretation):

Points are assigned based on the value of each parameter from 1 to 3, then summed. Survival assessment of patients with cirrhosis based on the total score:

Appendix G2. Calculation of the APRI fibrosis index

Title: Calculation of the APRI fibrosis score

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

Content: Calculation formula:

APRI = (AST / (AST ULN)) * 100 / platelets (10^9/L)

AST – patient's aspartate aminotransferase level; AST ULN – upper limit of normal for AST

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

Key (interpretation):

Appendix G3. Calculation of the FIB-4 fibrosis index

Name: FIB-4 fibrosis index calculation FIB-4

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. – №. 6. – P. e0199760.

Type: index

Content: Calculation formula:

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

Age – patient's age (years)

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

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

Key (interpretation):

Appendix G4. 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. – Vol. 10. – P. 155-170.

Type: scale

Content and key (interpretation):