New recommendations from the European Association for the Study of the Liver (EASL) for the treatment of hepatitis C with direct antiviral drugs

Is hepatitis curable?

Drugs with antiviral effects have been used to treat chronic hepatitis for more than 20 years. The point of their use is to eliminate the cause of the development of chronic hepatitis - to remove the virus. By removing the virus from the body, it is possible to stop the inflammatory process in the liver and prevent the progression of the disease to the development of cirrhosis and liver cancer. In recent years, significant progress has been observed in the global practice of treating chronic viral hepatitis, especially chronic hepatitis C. If with chronic hepatitis “B” it is possible to achieve a cure in 30-40%, and with chronic hepatitis “D” (delta) only in 15-20% of patients, then with chronic hepatitis “C” - in more than 70% of patients! But back in the early 90s of the last century, chronic hepatitis C was considered an incurable disease. At the early stage of antiviral treatment, its effectiveness barely reached 6-7%. Today, in the 21st century, a summary of the results of using modern treatment regimens and the latest drugs has shown that it is possible to cure 60-70% of patients with chronic hepatitis C. Thus, the effectiveness of treating this dangerous disease has increased 10 times!

Symptoms

The manifestations of the disease caused by genotype 1 in hepatitis C are quite diverse, but the course is cyclical and natural, going through several phases in its development:

1. Acute infectious. The primary stage, during which acute inflammation of the liver tissue is observed, provoked by the influence of the virus. Symptoms can be pronounced, but often the clinical picture is characterized by blurred signs or is limited to asthenovegetative syndrome. This period can end with recovery (about 30% of patients) or transition to a chronic form. Lasts up to six months.
2. Carriage. A person infected with hepatitis C without symptoms of the disease is called a virus carrier. The pathogen can still leave the body - that is, self-healing will occur. Otherwise, the virus carrier can become a source of infection for healthy people, and when the virus is activated, he risks being exposed to it himself. The carrier stage lasts from six months to several years.
3. Latent. The asymptomatic phase is why hepatitis C is called the “gentle killer.” The patient is unaware that the virus is slowly and irreversibly destroying his liver. The disease also has extrahepatic manifestations, which are very difficult to tolerate.
4. Razgara, or clinical. Occurs several months or years after infection. How long do people live with hepatitis C genotype 1b? This depends on the patient’s immune status and the presence of concomitant liver diseases.

It is the clinical phase that usually manifests itself with symptoms that cause patient complaints: weakness, persistent increase in body temperature for a long time, decreased or lack of appetite, nausea, vomiting, exhaustion as a result of weight loss.

The liver and spleen enlarge, there is pain and heaviness in the right hypochondrium, and resistance to physical activity decreases.

Jaundice syndrome is not always observed; it includes darkening of urine, lightening of stool, combined with yellow discoloration of the skin, mucous membranes and sclera of the eyes. Often the picture is complemented by skin itching.

Extrahepatic manifestations have a complex immune-mediated mechanism.

Among them are mixed cryoglobulinemia, periarteritis nodosa, nephropathies, rheumatoid arthritis, lichen planus, Hashimoto's thyroiditis, non-Hodgkin's lymphoma, idiopathic thrombocytopenia, etc.

Is it possible to predict the outcome of treatment?

It is known that the effectiveness of treatment depends on many factors. The genotype (variety) of the hepatitis C virus is of great importance. In Russia, genotype 1b is the most common, genotypes 1a, 2a, 3a are less common. The highest effectiveness of treatment (up to 95%) is in patients with genotypes 2a, 3a. The result of treatment also depends on the degree of activity of the virus (viral load). Therefore, studies of the genotype of the virus and quantitative analysis of viral RNA are mandatory before starting treatment. The effectiveness of treatment depends on the patient’s age, duration and stage of the disease (effectiveness is lower in patients with cirrhosis), the degree of alcohol consumption, the presence of obesity and some other factors. Extremely important in achieving a successful result are the patient’s readiness for treatment, full understanding with the attending physician (link to the schedule), strict adherence to the recommended doses of drugs and duration of treatment, regular monitoring of laboratory parameters and visits to the doctor in order to timely correct treatment. The doctor’s personal experience in applying modern treatment regimens developed in world science and practice is of great importance. Only many years of work experience allows us to individualize the approach to treatment, achieve its maximum result even in the most difficult cases, minimize side effects and prevent its premature cancellation. Extensive world experience shows that among patients with high adherence to treatment, which include patients who have received at least 80% of the recommended doses of medications for at least 80% of the recommended duration of treatment, the effectiveness of treatment exceeds 70%. The well-known factors that influence treatment effectiveness, listed here, help predict treatment outcome. However, the most reliable prediction of treatment success is based on determining the rate of disappearance of viral RNA when studied by polymerase chain reaction (PCR) in the first weeks of treatment.

Diagnostics

Methods for identifying subtypes of the first HCV genotype are standard and begin with general clinical tests: biochemical and liver tests, general blood and urine tests. As a rule, 1a and 1b are usually accompanied by an excess of liver enzymes and bilirubin. Less often, doctors pay attention to an increase in ESR and the level of certain blood elements.

Strictly specific research methods are:

• ELISA (allows you to determine the presence of certain antibodies, the production of which in the body begins as a result of the immune system’s reaction to blood contact with the virus). There are several types of research. Diagnosis should begin with determining the total antibody titer. If the result is positive, IgG and IgM should be differentiated, which determines the chronic or acute form of the pathology (respectively).
• PCR if positive ELISA results are obtained. A qualitative study demonstrates the presence of viral RNA in the body, a quantitative study demonstrates the level of HCV particles circulating in the bloodstream. This indicator is called viral load. The higher the figure obtained during the study, the more active the pathological process and the worse the prognosis regarding treatment results and the risk of complications.

In addition, genotyping of the hepatitis C virus is required to know whether the patient has type 1b or 1a. The result of this analysis is one of the key ones for determining further tactics of antiviral treatment.

Equally important is assessing the condition of the liver. Given its asymptomatic course, genotype 1 is often diagnosed at a late stage. First, liver tests and blood biochemistry, determination of bilirubin levels are prescribed. An ultrasound examination is also indicated, which will determine the size of the organ and the uniformity of the structure.

Fibrosis of the 3rd degree (its absence or another degree of severity) can be determined using modern non-invasive methods, for example, elastometry using the Fibroscan device. But the doctor receives the most complete information only through a microscopic examination of the biopsy obtained during the biopsy. In this way, it is possible to exclude or confirm malignant cell malignancy and the stage of oncological tissue damage.

Do I need treatment?

Chronic hepatitis C is very often detected during a random examination in people who consider themselves absolutely healthy. In such cases, patients often do not understand why they need expensive and lengthy treatment. Patients should be aware that hepatitis C is usually a slowly progressive disease. Liver cirrhosis develops on average 20-30 years after infection. However, in people who drink alcohol, drugs, or take medications that are “hard” on the liver, the formation of liver cirrhosis occurs much faster – within the first 10 years after infection. The “insidiousness” of the hepatitis C virus lies in the fact that for several years after infection a person can feel healthy, and sometimes the first symptoms of the disease appear only at the late stage of liver cirrhosis, when treatment is very difficult and the prognosis is unfavorable. After the formation of cirrhosis, the disease acquires a much faster rate of progression with the development of complications: jaundice, fluid accumulation in the abdomen, bleeding, and disturbances of consciousness. At this stage of the disease, more radical measures are required, in particular a liver transplant. In some patients, the hepatitis C virus affects not only the liver, but also other organs. It can cause the development of certain diseases of the blood, kidneys, joints, and skin even before the formation of cirrhosis of the liver. If a patient is diagnosed with chronic hepatitis C for the first time, this, of course, does not mean that treatment should be started immediately. However, you need to know that the effectiveness of treatment is higher in the early stages of the disease. Several years ago, when the effectiveness of antiviral therapy was significantly lower, treatment was not indicated for patients with normal biochemical parameters and low activity of the hepatic process according to liver biopsy. As a rule, patients with liver cirrhosis infected with genotypes 1a and 1b were not treated due to the very low effectiveness of antiviral therapy. Recently, with the use of the latest combination treatment regimens, the range of indications for antiviral therapy has expanded significantly. Antiviral treatment is indicated for most patients with chronic hepatitis C (including those with low disease activity and at the stage of compensated liver cirrhosis), with the exception of patients who continue to abuse alcohol and drugs and have contraindications to treatment.

Chronic viral hepatitis C

Features of the treatment of chronic viral hepatitis C. All patients with chronic hepatitis C are potential candidates for antiviral therapy. Treatment is recommended for patients at increased risk of disease progression to cirrhosis. In the European Association for the Study of Liver (EASL) and National Institutes of Health (NIH) guidelines, the indication for etiopathogenetic therapy is moderate to severe necrotizing inflammation and/or fibrosis of the liver with detectable levels of HCV DNA in the blood serum. These individuals are characterized by the presence of a histological picture of portal or interlobular fibrosis or low-grade inflammation and necrosis, and elevated ALT levels. In some patients, the risk factors and the degree of effectiveness of the therapy are not entirely clear, which requires additional research.

The goal of therapy for chronic hepatitis C is eradication of the virus, slowing the progression of the disease, improving the histological picture of the liver, reducing the risk of developing HCC and improving health-related quality of life.

Many of the patients are not included in the study due to drug use, alcoholism, age, and concomitant somatic and neuropsychiatric diseases. Efforts must be made to treat these populations. Since a large number of HCV-infected persons are in prison, a special approach is required for their prevention, diagnosis and treatment.

Treatment of patients should be carried out in centers that ensure compliance with sanitary and epidemiological regulations, by hepatologist specialists (infectious disease specialists and gastroenterologists). If patients have severe concomitant diseases caused by HCV, treatment should be carried out by hepatologists together with specialists according to the profile of the disease.

For etiopathogenetic therapy, antiviral drugs (interferons, cytokines), immunosuppressants (prednisolone, azathiaprine) and combination drugs (IFN + cytokines, or + ribavirin, or + interferon inducers), as well as, according to indications, other pathogenetic agents are used.

In the treatment of chronic viral hepatitis C, interferon is used in the phase of viral replication. The effects of IFN are due to the suppression of virus production and their elimination, immunomodulatory effect, increased expression of HLA antigens on cell membranes, increased cytotoxicity of T cells and natural killer cells, inhibition of fibrogenesis processes, and reduced risk of developing hepatocellular carcinoma. For the treatment of chronic hepatitis C, the following IFNs have been proposed: IFN-aga (reaferon, roferon A, etc.), IFN-aga (intron A, realdiron, etc.), lymphoblastic IFN-a, etc. Recently, the relatively recently created long-acting IFN has been widely prescribed actions (PegIntron, Pegasys), which can be administered subcutaneously once a week.

A positive effect from the use of interferons is observed with the following clinical and virological data:

• low level of aminotransferase activity in blood serum (increase no more than 3 times compared to normal);
• low level of HCV RNA in blood serum;
• portal or graded fibrosis of the liver in combination with moderate signs of inflammation and necrosis.
• absence of liver cirrhosis or its minimal severity;
• absence of cholestasis;
• normal iron levels in blood serum and liver tissue;
• short duration of HCV infection;
• HCV genotypes 2 and 3;
• infection with a homogeneous viral population, absence of HCV mutants;
• the patient's age is less than 45 years.

Interferons (roferon A, intron A, reaferon) are administered on average 3 million IU 3 times a week (every other day) subcutaneously or intramuscularly for 12 months, provided that HCV RNA disappears after 3 months from the start of treatment. If HCV RNA is detected after 3 months, it is not advisable to continue therapy according to the specified regimen. JAccording to the recommendations of the Russian consensus of 2000, the basis for IFN monotherapy is:

• young age at the time of infection (up to 40 years);
• female;
• lack of excess body weight;
• absence of elevated iron levels and increased GGTP activity in the blood serum;
• elevated ALT level;
• the presence of a moderate degree of process activity and minimal fibrosis in the liver;
• low level of HCV RNA and not 1 genotype of hepatitis C virus

The absence of these factors can be considered as an indication for combination therapy.

Favorable factors for interferon therapy are also the duration of the disease no more than 5 years, the absence of histological signs of liver cirrhosis, the absence of alcoholism (normal level of anti-inflammatory drugs), drug addiction, the absence of co-infection with HBV and HIV, an increased level of ALT in the presence of HCV RNA in the serum.

Unfavorable factors affecting the effectiveness of inferon therapy are the duration of the disease over 5 years, the elderly age of the patient, and pronounced histological changes in the liver puncture.

Contraindications to interferon therapy:

Absolute:

• severe depression or a history of depression;
• uncontrolled epilepsy or seizure disorder;
• thrombocytopenia (less than 50,000 cells in 1 μl), leukopenia (less than 1500 cells);
• organ transplantation (except liver);
• the presence of decompiled liver cirrhosis;
• severe heart disease.

Relative:

• severe concomitant diseases of the lungs, kidneys, cardiovascular system, decompensated diabetes mellitus;
• uncorrectable thyroid diseases;
• alcohol abuse;
• mental illness, including a history;
• autoimmune hepatitis and severe virus-induced immune disorders;
• concomitant autoimmune diseases;
• AIDS;
• addiction;
• malignant tumors;
• the presence of autoantibodies to mitochondria and other cellular and subcellular structures.

The criteria for the effectiveness of treatment are the normalization of the disappearance of HCV replication phase markers (HCV RNA, HCVAb IgM).

Level of aminotransferases, histological picture of the liver. The rate of positive response to treatment is 40-50%.

Thus, determining the clinical effectiveness of therapy includes assessing the early response to its implementation, as well as the results of treatment immediately after its completion and for a sufficiently long period of time thereafter. When assessing the effectiveness of therapy, the following recommendations should be followed:

• Early virological response is determined by calculating the percentage of patients with a negative qualitative HCV-RNA test result 12 weeks after the start of antiviral therapy.
• The primary response is defined as the percentage of patients with a negative qualitative test result for HCV-RNA and normalization of ALT immediately after completion of the course of antiviral therapy.
• Sustained virological response (sustained biochemical and virological remission) is defined as the percentage of patients with a negative result of a qualitative analysis for HCV-RNA and normalization of ALT 24 weeks after completion of therapy.

The effectiveness of interferons in chronic viral hepatitis C is increased by the combined use of ribavirin at a dose of 800-1200 mg, ursodeoxycholic acid at a dose of 600 mg/day, and essential phospholipids. For interferon-resistant HCV lb hepatitis, interferon-a is administered for the first 6 months at a dose of 6 million IU three times a week. Stable remission is observed in 35-40% of cases. For patients with partial remission, a repeat course lasting up to 1.5-2 years is indicated.

According to the recommendations of the conference on the management of patients with hepatitis C, held in Paris in February 2002, patients with HCV genotype 1 should continue treatment for 48 weeks, provided that after 12 weeks of treatment the virus is undetectable or its titer has decreased by more than 2 lg copies. If there is no effect of treatment, the purpose of which was to eradicate the virus, it may be discontinued. To reduce the rate of development of the disease, it is possible to continue the course. Patients with genotypes 2 and 3 are shown the usual course of combination therapy (IFN + RBV) for 24 weeks. For genotypes 4, 5, 6, a treatment period of up to 48 weeks is recommended, taking into account the risk-benefit ratio of the therapy, assessed individually.

The effectiveness of the use of pegylated interferons is confirmed by the fact that when PegIntron was administered once a week (in all Lozas), an immediate and sustained virological response was observed much more often than when using intron A. At the same time, virological effectiveness at the end of treatment with PegIntron depends on the dose. Use of the drug at a dose of 1.5 mcg/kg once a week increases the rate of sustained virological response by 2 times.

Administration of PegIntron once a week is more effective than monotherapy with introintestinal A. In patients who responded to treatment, a significant improvement in the histological picture of the liver was detected compared with patients in whom there was no effect. A decrease in the degree of fibrosis can be observed in patients with F3/F4 stages of the disease.

Thus, the development of pegylated forms of IFN with improved pharmacokinetics, higher efficiency compared to standard interferons and a more convenient dosage regimen (once a week) provided patients with a higher chance of cure. The use of pegylated interferons has reduced the incidence of side effects typical of standard interferon treatment regimens.

Although SVR does not have a strong correlation with patient survival due to the need for long-term follow-up, the absence of detectable HCV RNA indicates a decrease in the severity of liver damage, decreased fibrosis and minimized risk

occurrence of recurrent disease. In addition, two large studies conducted in Japan showed that interferon treatment is associated with a reduced risk of developing HCC, which is important for those who achieve SVR.

Patients who fail to achieve SVR are given a second course of treatment. The decision on this is based on the following main points:

• the nature of the previous answer;
• the type of previous therapy and the potential for a new type of treatment;
• severity of liver damage;
• virus genotype and the presence of other prognostic factors;
• tolerance to previous therapy.

The possibility of achieving SVR in patients receiving re-treatment with pegninterferon in combination with ribavirin after monotherapy, or using a standard interferon/ribavirin treatment regimen, is currently being discussed. However, continuing repeated therapy without adjusting the treatment regimen may lead to a decrease in the effectiveness of therapy.

Patients who do not respond to peginterferon/ribavirin therapy at optimal doses pose a serious problem, especially in the presence of liver fibrosis or cirrhosis.

Patients with advanced fibrosis or cirrhosis are at increased risk of developing liver decompensation and should be considered candidates for re-treatment, especially if monotherapy is ineffective. Patients with moderate fibrosis and active liver disease should be given repeat therapy.

Approximately 30% of patients with HCV infection have normal ALT levels, and 40% have enzyme activity levels 2 times higher than the upper normal level. Despite mild histological changes, most of these patients tend to progress to liver fibrosis and cirrhosis.

Patients with normal ALT levels, minimal and weak otological activity of hepatitis without fibrosis can be subject to dynamic observation without antiviral treatment (control examination once every 6 months).

When carrying out etiopathogenetic treatment, it is necessary to remember the possibility of developing such side effects as pyrogenic

reaction and flu-like syndrome, depression, insomnia, asthenic syndrome, headache, skin itching and rash, alopecia, anorexia, as well as changes in clinical blood tests - neutropenia, thrombocytopenia, anemia. Changes in biochemical parameters are also possible: increased activity of alkaline phosphatase, LDH, increased levels of creatinine and urea nitrogen in the blood serum.

The development of influenza-like syndrome can be prevented by taking paracetamol (no more than 3 g/day) or ibuprofen (in the absence of cirrhosis) simultaneously with the IFN injection.

Among the severe complications of interferon therapy, mental disorders are often observed. Often, during etiopathogenetic therapy, severe depression develops, requiring emotional support, psychotherapeutic assistance, and sometimes the prescription of antidepressants from the group of serotonin reuptake inhibitors.

To avoid the development of insomnia, ribavirin should be taken in the evening, but not at night. In severe cases, the use of tricyclic antidepressants is recommended.

Changing your lifestyle, physical activity, and increasing the volume of fluid intake will help stop the formation of asthenic syndrome.

Skin itching and rashes observed with the above treatment can be treated with antihistamines and ointments based on glucocorticosteroids.

The alopecia that is sometimes observed is reversible; in these cases, it is useful to conduct psychotherapeutic conversations with patients.

With the development of anorexia, the diet is supplemented with enriched nutritional mixtures, and if necessary, prokinetics are prescribed.

Myalgia can be relieved by taking non-steroidal anti-inflammatory drugs (in the absence of contraindications to them).

If neutropenia develops, it is recommended to adhere to the following rules:

• If the absolute number of neutrophils decreases to less than 750 cells/μl, it is necessary to consider reducing the dose of interferon by 2 times.
• In case of neutropenia with an absolute cell count of less than 500/μl, treatment should be interrupted until the absolute number of neutrophils increases to 1000/μl.

The development of thrombocytopenia requires appropriate medical tactics:

• If the platelet count decreases to less than 50,000 cells/μl, it is recommended to reduce the dose of IFN-a by 2 times.
• In cases where the absolute platelet count decreases to less than 25,000 cells/µl, treatment should be interrupted.

If anemia is detected (decrease in hemoglobin level < 10 g/l, but 8.5 g/dl) during antiviral treatment, the dose of ribavirin is reduced to 600-800 mg/day. In patients with diseases of the cardiovascular system, the dose of the drug is reduced in the same way when hemoglobin drops more than 2 g/dl from the initial level or when its level is <12 g/dl. If complaints of weight loss and fatigue appear, it is necessary to examine the function of the thyroid gland (blood test for antibodies to thyroglobulin and antithyroid peroxidase activity of blood serum) every 2 months. In patients with a history of thyroid dysfunction, TSH monitoring should be performed once a month.

During treatment, autoimmune diseases may worsen: autoimmune hepatitis, idiopathic thrombocytopenia, hemolytic anemia, diabetes mellitus. Other autoimmune syndromes and diseases that arise or manifest during the administration of IFN-a include psoriasis, rheumatoid arthritis, SLE-like syndrome, sarcoidosis, and PBC. It is difficult to predict the occurrence of such complications. Before starting therapy, it is necessary, firstly, to carefully verify the diagnosis of hepatitis C and, secondly, to determine the initial spectrum of autoantibodies as completely as possible. The increased risk of developing autoimmune complications in patients with HLA haplotypes DR3, DR4, DR52 and DQ2, i.e., haplotypes associated with autoimmune hepatitis and other autoimmune diseases, should be taken into account. To monitor IFN therapy, a monthly clinical examination of the patient is recommended to determine the activity of transaminases (AlAT, AST) and other biochemical parameters, as well as a hemogram.

It should be noted that side effects such as anemia, weakness, depression are significantly more often observed with combination therapy.

HCV infection is common after liver transplantation, and the extent to which it progresses depends on the patient's immune status. The frequency of recurrent HCV infection correlates with the viral load at the time of surgery, the age of the donor, and the severity of immunosuppression in a particular individual in the postoperative period.

Biochemical remission at the end of treatment is assessed by the normalization of ALT. After completion of therapy, the criteria for complete remission are normalization of ALT levels and the disappearance of HCV RNAhi in the blood.

With IFN therapy, some patients may develop relapses of chronic hepatitis C during treatment, which, according to some authors, is due to the formation of antibodies to reaferon. In such cases, it is advisable to check for the presence of antibodies to IFN and, if they are detected, discontinue reaferon and continue treatment with natural leukocyte interferon.

Stable biochemical remission means the preservation of normal ALT activity 6 months or more after cessation of therapy. Stable complete remission in patients with chronic hepatitis C includes normal activity of AST, ALT, absence of HCV RNA 6 months or more after cessation of therapy.

If the patient does not respond to interferon therapy within 3 months of treatment, i.e., he continues to have hyperfermentemia and viremia, then IFN treatment should be discontinued. Virological control is carried out at the 12th week (3 months) of treatment.

If, after completing a 6- or 12-month course of IFN therapy, a relapse of the disease occurs, a second course of IFN treatment is possible, the response to which may be higher than the first. IFN-os is re-prescribed at a dose of 3 or 5 million IU per day intramuscularly 3 times a week for at least another 12 months. With this continuous repeated course of treatment, a response is achieved in 40-80% of patients.

However, if by the end of a 6-month course of IFN therapy only ALT activity normalized and viremia did not disappear, then with repeated IFN therapy only ALT normalizes, and HCV RNA rarely disappears in them.

Response to treatment is considered durable if a negative HCV RNA test and normal ALT levels are observed 6 months after completion of the full course of treatment.

Currently, to increase the effect of a repeated course of IFN therapy, a combination of IFN-a with ribavirin is used at a dose of 14 mg/kg per day.

Even in patients who did not respond to the first course of IFN therapy, a repeated course combined with ribavirin allows obtaining a positive response in 20-25% of cases. In individuals who responded to the first course of interferon therapy (at least transiently), repeated treatment combined with ribavirin increases the effect to 50-70%.

If stable complete remission is achieved 6 months after the end of treatment, it is recommended to continue monitoring the patient for at least 2 years with a frequency of 1 time in 6 months and subsequent liver biopsy.

As noted above, ribavirin (arviron, virazole, rebetol, ribavin, ribamidil), an analogue of guanosine, is widely used in the treatment of patients with chronic hepatitis C. The drug has a virusostatic effect against many DNA and RNA viruses, including those that are not sensitive to other antiviral drugs. The use of ribavirin for chronic hepatitis C does not reduce viremia, but has an immunomodulatory effect and, possibly, an immunosuppressive effect, normalizes ALT levels and improves the histological picture of the liver. Monotherapy with ribavirin for a year is relatively well tolerated by patients.

Only in 10-15% of cases the drug gave adverse reactions in the form of fatigue, dizziness, nausea, itching of the skin, and in a number of patients - hemolysis with a subsequent increase in serum iron content, as well as an increase in the concentration of iron in hepatocytes, which is known to contribute to the progression of fibrosis and deterioration in the effectiveness of IFN therapy. Ribavirin is taken orally at a dose of 1200 mg per day, divided into two doses (morning and evening).

Contraindications for the use of ribavirin are severe diseases of the cardiovascular system, thyroid gland, hemoglobinopathies, chronic renal failure, autoimmune hepatitis and decompensated liver cirrhosis, pregnancy, and age under 18 years. When using the drug, it is advisable before starting treatment, and then at the 2nd, 4th, 8th week of treatment and then regularly, as necessary, to conduct a clinical blood test (erythrocytes, leukocytes, leukocyte formula, platelets), a study of electrolytes, determination of creatinine levels, performing liver function tests. Women of childbearing age should use effective contraceptives for 6 months after treatment.

Some drug interactions have been described for ribavirin. Thus, when taken simultaneously with products containing magnesium and aluminum or simethicone, the bioavailability of the drug decreases,

Contraindications to antiviral therapy for chronic hepatitis with ribavirin are divided into absolute and relative.

Absolute contraindications:

• end-stage renal failure;
• anemia and hemoglobinopathies;
• pregnancy and lactation;
• non-compliance with contraception during treatment;
• uncompensated diseases of the cardiovascular system.

Relative contraindications:

• hypersensitivity to ribavirin;
• thyroid diseases;
• hemoglobinopathies (thalassemia, sickle cell anemia);
• epilepsy;
• decompensated cirrhosis of the liver;
• autoimmune hepatitis, other autoimmune diseases;
• age under 18 years;
• elderly age;
• uncontrolled arterial hypertension;
• hemoglobin level <12 g/l in women and <13 g/l in men.

The optimal antiviral treatment regimen includes pegylated interferon-a2a at a dose of 180 mcg per week or pegylated interferon at a dose of 1.5 mcg/kg body weight per week + ribavirin in doses corresponding to body weight. The duration of treatment depends on the HCV genotype.

If a relapse occurs and in the absence of contraindications to ribavirin, it is recommended to start combination therapy with IFN + ribavirin for 6 months or a repeat course of monotherapy at a dose of 3 million IU for 12-18-24 months. In both cases, a permanent response can be obtained in 60% or more of patients. Combination therapy for recurrent chronic hepatitis C is 10 times more effective than IFN-a monotherapy.

It should be noted that ribavirin can cause side effects (fatigue, depression, dizziness, nausea, itching), and it is also possible to develop hemolysis with a subsequent increase in the concentration of iron in the blood serum and in liver cells. In turn, the accumulation of iron in hepatocytes increases fibrosis and reduces the effectiveness of therapy. To prevent the development of such an effect, it is advisable to carry out vomiting before carrying out combination therapy, primarily in those patients who, even before the combination therapy, had an increase in iron levels in the blood serum. We have proposed a treatment regimen for such patients with preliminary cytapheresis. In the treatment of chronic viral hepatitis, interferon inducers, in particular cycloferon, are also used. The drug is prescribed intramuscularly in a dose of 2 ml on days 1, 2, 4, 6, 8, 10 and 12 of the course of treatment, followed by switching to oral administration. A combination of cycloferon and interferon is advisable.

The use of ursodeoxycholic acid in the treatment of chronic hepatitis C is an adjuvant. In the presence of cholestasis syndrome, UDCA reduces the incidence of biochemical relapse of hepatitis.

Currently, studies are being conducted on the effectiveness of treating chronic hepatitis C with the following drugs in monotherapy, as well as in combination with pegylated interferons

• interleukin-2, -12,
• amantadine,
• mycophenolate mofetil,
• dihydrochloridagistamine,
• thymosin-a,
• VX-497.

The coincidence of the spectrum of pharmacodynamic activity of interleukin-2 (rIL-2) with the structure of immune dysfunctions in chronic hepatitis C justifies its use in treatment regimens for this disease. The domestic drug roncoleukin contains recombinant human IL-2 (rIL-2) as an active principle. The immunotherapeutic effect of rIL-2 is realized by replenishing the deficiency of endogenous interleukin-2, stimulating clonal proliferation of immunocompetent cells, prolonging the life of activated immunocompetent cells by reducing the level of apoptosis, restoring the Tm/Tn2 balance and correcting the cytokine regulation profile, increasing the functional activity of mononuclear phagocytes and production of endogenous interferons.

The use of roncoleukin in monotherapy is carried out according to two treatment regimens:

• Scheme I - intravenous administration of the drug 0.5 mg 2-3 times a week for 8 weeks; only 16-24 injections,
• Scheme II - intravenous administration of the drug 0.5 mg 3 times a week for the first two weeks and further subcutaneous administration of 0.5 mg 3 times a week for the remaining 6 weeks, a total of 24 administrations.

Currently, the largest amount of data on the feasibility and effectiveness of treating patients with chronic hepatitis C with roncoleukin, as well as its tolerability, has been obtained using a monotherapy regimen

A regimen of combination therapy with roncoleukin in combination with IFN-a drugs was first proposed and pathogenetically substantiated for the treatment of patients with chronic hepatitis C who have minimal biochemical histological activity of the process, including for patients who have not responded to interferon therapy. According to this scheme, roncoleukin is prescribed during treatment with IFN-a drugs intravenously at 0.5 mg 2 times a week for the first 8 weeks; 16 introductions in total.

During treatment with roncoleukin, the viral load decreases, including in monocytes, and the histological picture of the liver improves. The drug promotes the activation of the initially reduced cellular component of immunity and has a modulating effect on the humoral component. It should be noted that the drug was well tolerated and there were no serious side effects. A short-term increase in temperature to subfebrile values ​​during its administration was observed in 14% of patients.

The accumulated experience has made it possible to determine the principles of roncoleukin therapy:

• possibility of use in patients with contraindications to IFN therapy;
• possibility of use in patients with minimal histological and biochemical activity of the pathological process;
• the possibility of combining IFN and its inducers with drugs, overcoming the developing resistance to them.

According to Italian clinicians, in the majority of patients with chronic hepatitis C who have not previously responded to interferon-a monotherapy, combination three-component therapy - interferon-a + ribavirin + amantadine (midantan, symmetrel) - can be effective. Based on the results of their clinical study, it was concluded that the addition of amantadine hydrochloro-RVDA (200 mg per day orally) to interferon-osr therapy in combination with ribavirin more than doubled the number of patients in whom, after 12 months treatment, a clear response to therapy was achieved (up to 68%). Moreover, a year after the end of three-component therapy, a stable response occurred in 25% of patients, while among patients receiving two-component treatment, this figure did not exceed 4%.

A pharmacological substance with the working name VX-497 is at the stage of clinical trials, which is similar in its mechanism of action to ribavirin, but, according to the developers, is ten times more effective than it

Treatment of chronic hepatitis C patients with concomitant diseases requires a special approach and the development of special interferon therapy tactics. It is important to make sure that the use of interferon is appropriate for a particular patient (the presence of HCV replication, a persistent or wave-like increase in AST activity in combination with moderate or pronounced morphological activity in the liver). It is important to evaluate the leading pathology. The decisive factor may be the rate of progression of the concomitant disease. If it develops rapidly, treatment of chronic HCV infection with interferon in most cases should be abstained.

In this regard, one should also remember the likelihood of drug interactions between interferons and other medications taken by the patient, especially since they have not been fully studied. Use interferon-a with caution simultaneously with opioid analgesics, hypnotics and sedatives, and with drugs that potentially have a myelosuppressive effect. Interferons can influence oxidative metabolic processes. This should be taken into account when administered simultaneously with drugs that are metabolized by oxidation (including xanthine derivatives - aminophylline and theophylline). When using interferon simultaneously with theophylline, it is necessary to monitor the concentration of the latter in the blood serum, and, if necessary, adjust the dosage regimen. Combination with chemotherapeutic drugs (cyclophosphamide, doxorubicin, teniposide) increases the risk of developing toxic side effects and interferon therapy 1 severity and duration), which can seriously threaten the patient’s life.

For the treatment of chronic hepatitis C in patients with cancer, standard doses of IFN can be used subject to the following conditions: the presence of clinical, laboratory and morphological indicators of hepatitis C activity, remission of the underlying disease, and the absence of chemotherapy or radiation therapy.

Experimental studies have revealed the toxic effect of interferon therapy on the reproductive function of animals. The significance of this data for humans is unknown. However, CHCV is not treated with etiotropic drugs during pregnancy. Infection of a child is possible if the mother has active viral replication during pregnancy and childbirth, but even in this case, the vertical mechanism of transmission of the disease is realized only in 4-10% of cases.

It is not known whether the components of interferon-a preparations are excreted in breast milk. Due to the possible risk of adverse reactions in breastfed infants, if interferon therapy is necessary, the mother should stop breastfeeding. Women of childbearing potential should use reliable methods of contraception during treatment with interferon drugs.

Treatment of chronic hepatitis C in patients with autoimmune disorders is currently not well developed. Therapy with interferon drugs in these cases should be strictly individual. In case of pronounced clinical and laboratory manifestations of an autoimmune disease at the beginning of treatment, preference should be given to prednisone therapy.

Recent research results have demonstrated the effectiveness of treatment for people who inject drugs. This is very important, since injection drug addicts make up the majority of patients with hepatitis C. Their successful treatment will significantly reduce the spread of HCV infection.

Alcohol is an important cofactor in the progression of HCV infection to cirrhosis or HCC. A history of alcoholism is not a contraindication to treatment, but drinking alcohol during a course of medication increases side effects. It is necessary to strongly advise patients to stop drinking alcohol or at least reduce its dose to 10 g or less per day. It is very important to begin therapy for alcohol dependence before starting treatment for hepatitis; antiviral therapy in such individuals is considered only as part of a comprehensive treatment of the underlying disease.

Forecast

The most serious consequences of chronic HCV infection are liver fibrosis progressing to cirrhosis, end-stage liver disease, and HCC. The incidence of liver cirrhosis 20 years after acute infection is 17-55% in retrospective studies and 7-16% in prospective studies. However, no significant influence on the risk of liver disease progression has been established for such virological factors as viral load, genotype and the number of quasispecies. The risk of developing severe complications increases with infection in older people, males, the presence of immunodeficiency conditions, hepatitis B. An important role in the development of complications is played by regular consumption of more than 60 g per day of alcohol (6 glasses of beer, 4 glasses of wine or 3 cocktails) for men and 40 g per day for women. A negative impact on the course of the process can be caused by increased iron content, non-alcoholic liver steatosis, schistosomal co-infection, taking potentially hepatotoxic drugs, and the presence of environmental pollution.

Side effects are possible but easily controlled.

Patients should be aware that the general health of most patients during treatment is somewhat worse than before treatment. This is due to the possibility of developing such side effects as increased temperature (at the beginning of treatment), decreased hemoglobin levels, changes in the state of the nervous system (irritability, insomnia, decreased mood), changes in thyroid function. Appetite decreases and, as a rule, there is a slight weight loss. Less common concerns include dry skin and rashes, dry mucous membranes, and cough. All side effects are monitored by a doctor and are not life-threatening. Some side effects may require additional medications, for example, drugs to regulate the function of the thyroid gland, the nervous system, and to increase hemoglobin levels. All side effects completely disappear in the first weeks after completion of treatment.

How to determine the genotype?

The first genotype of hepatitis C, like other forms of this disease, is transmitted through blood. Therefore, the leading way to determine the disease is a blood test.

To determine which type of hepatitis you are infected with, take a test called HCV Genotyping .

Attention! The genotype cannot be determined by tests for Antibodies, Qualitative PCR or Quantitative PCR.

Use only Genotyping .

You can undergo complex diagnostics to determine the genetic type of hepatovirus in the following clinics:

How to prepare for the upcoming test to determine genotype 1c? Below are recommendations from specialists at the International Clinic Freiburg:

• Refuse to eat 8 hours before reporting to the laboratory.
• Do not drink alcohol for 48 hours before donating blood.
• Avoid stress and eating fatty foods in large quantities.

Based on the test results, treatment methods for hepatitis C are determined that are suitable for a specific genetic type of the virus.

Is there an alternative to antiviral treatment?

To date, there is no alternative to antiviral treatment. There are a number of drugs that are offered as alternatives to antiviral treatment, but none of them have been proven to eliminate the virus and cure the disease. Our century is a century of rapidly developing medical technologies. Over the past two decades, dozens of new drugs that have an antiviral effect against various viral infections have been developed and began to be used. New antiviral drugs are also being developed for the treatment of chronic hepatitis C. They will appear, apparently, in a few years. But today we can say with confidence that a diagnosis of hepatitis is not a death or life sentence. The desire of the patient and the professionalism of the doctor today can defeat the disease and return the body to a clear and cloudless sky of health.

Frequency of occurrence of various HCV genotypes in the world

Prevalence of different HCV genotypes

Genotypes 1 (subtype 1b) and 3 are the most common. They are detected in 46.2% and 31% of all cases of hepatitis C, respectively. In the Republic of Belarus, the main share of HCV infection is caused by genotype 1 (> 75% of all cases). Epidemiological data indicate that the global spread of genotype 1 began from the regions of West Africa and Southeast Asia after the First World War and increased significantly after the Second World War, which is associated with the widespread use of blood and components, the infectious safety of which was not controlled during the years of military battles. (Nokano T., 2004), (Holmes EC., 2008).

Treatment regimens for virus genotype 1

For decades, the only cure for HCV was pegylated Alpha-Interfron in combination with Ribavirin. The duration of the therapeutic course ranged from 6 months to 1 year. As a result, serious complications were observed that directly affected the patient’s condition and health. In particular:

• Complete or partial hair loss.
• Changes in the biochemical composition of the blood.
• Functional kidney disorders.
• A sharp decrease in immunity.

Due to the risk of developing pernicious anemia, the patient has to regularly undergo blood tests to check its composition. At the slightest change, the therapeutic course will have to be urgently interrupted. The treatment process requires constant supervision of the treating specialist.

Due to lack of effectiveness and a large number of side effects, interferon regimens are not used in modern hepatology. They have been replaced by innovative therapeutic methods based on Sofosbuvir. This medicine is not taken as a monotherapy. Depending on the genetic type of the virus, Ledipasvir, Daclatasvir or Velpatasvir are taken in tandem with it.