RU2475263C1 - Method of treating chronic viral hepatitis c with medications in liposomal form - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine and deals with method of treating chronic viral hepatitis C, which includes oral introduction into organism of liposomal medication alpha-2 interferon in from of "Reaferon-EU-Lipint" and liposomal medication ribavirin in form of "Ribavirin-LIPINT", as well as introduction into organism of injection form of alpha-2 interferon in form of "Reaferon-EU".

EFFECT: invention ensures reduction of treatment terms by increasing efficiency of antiviral action of complex of medications, applied in accordance with claimed method of treating chronic viral hepatitis C without increasing toxic impact on patient's organism.

2 cl, 1 ex, 5 tbl

Description

The invention relates to methods for treating patients with chronic viral hepatitis C and can be used in medicine and virology.

A known method of treating viral hepatitis C using recombinant interferon-alpha (IFN-alfa). According to this method, the administration of IFN-alfa subcutaneously, intramuscularly, leads to a persistent clinical effect in 10-25% of cases [Fried M.W., Hoofhagle I.H. Therapy of hepatitis C - Semin. Liver. Dis., 1995, v. 15, No. 1, p. 82-91]. The method is used to treat hepatitis C in adults by administering IFN-alfa at a dose of 3 to 10 million ME 3 times a week for 0.5-1 years, depending on the genotype of the virus.

The disadvantages of the method are its low therapeutic efficacy, the inability to prevent and treat extrahepatic manifestations of the disease. So, the virological response to treatment is only 19%, and when using the pegylated form of the drug (pegasis) - 39%.

Currently, in the practice of treating chronic viral hepatitis C, therapy is used based on the use of interferon in combination with drugs that enhance its therapeutic effect, in particular such as thymosin [RF Application No. 94022480, IPC A61K 38/04, publ. July 20, 1996].

Such therapy is quite effective and provides a stable virologic response rate in the treatment of patients at the level of 40-50%. However, as practice shows, some patients do not respond to interferon therapy.

This is due to the fact that hepatitis C viruses have a specialized defense mechanism against interferons, based on the ability of viruses to synthesize various proteins that mimic the function of cellular proteins. The appearance of these proteins in infected cells leads to the blocking of the activation signal from interferon receptors necessary to trigger antiviral protection [Cell. 1992. Vol. 71, p. 5-7; J. Virology. 1999. V.73, No. 10, p. 8469-8475].

A known method of treating hepatitis C using the antiviral drug ribaverine (see, for example, US Patent No. 4211771, IPC A61K 31/41, 1980 or RF Patent No. 2255735, A61K 31/41, 2005).

The disadvantage of this method is the low therapeutic efficacy (about 25%), the inability to prevent and treat extrahepatic manifestations of the disease.

A known method of treating hepatitis C using a combination of recombinant IFN-alfa-2 and ribavirin, which gives a synergistic effect. This method is recognized as the most effective treatment option for chronic hepatitis C [Fried M.W., Shiftman M.L., Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engi J. Med. 2002; 347 (13): 975-82].

However, this method has insufficient therapeutic efficacy. So, the virological response to treatment is only 44%, and when using the pegylated form of the drug (pegasis) - 56% [Manns M.P., McHutchison J.G., Gordon S.G., et al. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multi-center, multinational phase III randomized controlled trial. Hepatology. 2000; 32: 297A or I.S. Nikolayev, V.V. Petere. Chemical Pharmaceuticals Journal, 2002, No. 5, p. 55]. Given the cost of drug treatment (about $ 2,500 per month), the price-quality ratio of such treatment is extremely low. The course of treatment is from 6 months. up to 1 year

The closest analogue (prototype) is a method of using liposomal forms of interferon-alpha and ribavirin in the form of multivisicles for the treatment of hepatitis C virus (WO 2009009115, IPC A61K 38/21, publ. 2009-01-15). However, this method of treatment of hepatitis C virus has a long course of therapy (up to 12 months) with a significant reduction in toxicity to the body, as confirmed by preclinical studies in animal models that use rats.

The technical result of the claimed invention is to reduce the duration of treatment by increasing the effectiveness of the antiviral effect of the complex of drugs used in accordance with the claimed method of treating chronic viral hepatitis C without increasing toxic effects on the patient's body.

The specified technical result is achieved by the fact that in the method for the treatment of chronic viral hepatitis C drugs in liposomal form, including oral administration to the body of liposomal preparations of alpha-2 interferon and ribavirin, according to the invention, it includes the additional introduction into the body of an injectable form of alpha-2 interferon in the form Reaferon-EU at a dose of 3 million ME, subcutaneously, 3 times a week, Reaferon-EU-Lipint is used as a liposomal preparation of interferon alpha-2, and Riba as a liposomal preparation Irina use “Ribavirin-LIPINT”, which is administered according to the following scheme: “Ribavirin-LIPINT” 1000 mg daily and “Reaferon-EU-Lipint” 1 million ME 2 times a day in the morning and evening every other day with a course of treatment that ensures achievement stable clinical and laboratory remission.

The course of treatment with liposome preparations and the injectable form of alpha-2 interferon "Reaferon-EC" is not more than 6 months.

Reaferon-EU-Lipint

The drug "Reaferon-EU-Lipint" (registration certificate P N000821 / 01 of 03/19/2007, LSR-000011 of 03/20/2007, the validity period is unlimited), manufacturer ZAO Vector-Medica, Novosibirsk. The active substance interferon-alpha 2 is recombinant, enclosed in a liposomal membrane (a microcapsule made from natural phospholipids), which protect it from destruction in the gastrointestinal tract.

Advantages of Reaferon-EU-Lipint:

- the most convenient and natural route of administration of the drug is oral;

- the absence of side effects characteristic of the injectable use of recombinant interferon with the same antiviral efficacy;

- increased, compared with the injectable form of recombinant interferon, the induction of interferon;

- does not contain albumin, unlike other interferon preparations, which positively affects the safety of the drug and contributes to:

1) a significant decrease in the production of antibodies to interferon with prolonged treatment, which leads to an increase in the effectiveness of the therapy;

2) eliminates the risk of infection through blood-borne infections (hepatitis, HIV infection, herpes viruses, cytomegalovirus infections, etc.);

3) the ability to use interferon preparations in individuals with increased allergy to serum proteins.

The best treatment results are observed in patients receiving Reaferon-EU-Lipint in combination with an injectable form of interferon, this allows to increase the total dose of administered interferon [Gavrilova NI, Filimonov PN, Cherepanova NS, Targonsky S .N., Usova S.V. / Results of a study of the efficacy and safety of reaferon-EU-Lipint and Lifeferon in children with chronic hepatitis C / 16 Congress "Man and Medicine" Abstracts 2009_С-426].

Ribavirin is an orally administered synthetic nucleoside. It was established that with monotherapy it does not affect the viral load of HCV or histological changes in the liver, however, the combined administration of interferon-alpha and ribavirin at a dose of 400-1200 mg per day to patients with viral hepatitis C increases the degree of response to 60% or more.

According to experts from the Cochrane group [for the study of liver diseases (Brok J., et.al., 2005)], an analysis of 72 clinical trial protocols (sample included 9991 patients) using interferon + ribavirin revealed a histological and virological response in 40% of patients. At the same time, a lot of undesirable reactions (hematological, dermatological, gastroenterological types) that arose during therapy were noted, negatively affecting the quality of life of patients. In 56% of cases, T. Nacamura et.al. indicate marked side effects with drug withdrawal in their studies. (2005), Y. Iwasaki (2006).

The mechanism of action of Ribavirin is the competitive inhibition of inosine monophosphate dehydrogenase, which leads to inhibition of the synthesis of viral RNA and DNA. Moreover, ribavirin selectively inhibits the synthesis of viral RNA without inhibiting the synthesis of RNA in normally functioning cells. Ribavirin easily penetrates into the affected cells and is rapidly phosphorylated by intracellular adenosine kinase to ribavirin mono-, di- and triphosphate. These metabolites, especially ribavirin triphosphate, have a pronounced antiviral activity. Ribavirin inhibits the replication of new virions, which reduces the viral load. Ribavirin preparations are effective against many DNA and RNA viruses that are not sensitive to other antiviral drugs. Of the DNA-containing viruses, the most sensitive to ribavirin are: Simple herpes virus, poks-virus, virus Mareks illness; and from RNA viruses, Influenza AB, paramyxovirus.

Since ribavirin has been on sale for several years, many dosage forms and routes of administration are known, and all acceptable dosage forms and routes of administration can be used. The main method of application is oral administration at the rate of 15 mg per 1 kg of body weight, which corresponds to 800-1200 mg per day. Ribavirin is easily absorbed after ingestion of a single dose of the drug (Tmax = 1.5 hours), after which it is rapidly distributed in the body. Absolute bioavailability is approximately 45-65%. There is a linear relationship between dose and bioavailability when taking single doses of ribavirin in an amount of 200 mg to 1200 mg. Ribavirin does not bind to plasma proteins.

Ribavirin is excreted slowly from the body - after cessation of administration, the half-life is about 298 hours, which indicates its delayed excretion from other parts of the body, except for plasma. 10% is excreted in the urine.

Despite the high antiviral activity against many viruses, ribavirin preparations (Vero-ribavirin, Ribavirin Meduna, Virazol, Rebetol, Ribamidil, Ribavirin-Bio) have not been widely used in healthcare practice due to their pronounced toxicity and are widely used only for the treatment of chronic hepatitis C in combination with interferon-alpha drugs.

The toxic effects of Ribavirin do not allow it to be prescribed to children and adolescents under 18 years of age, elderly patients over 60 years old, pregnant women, patients with severe heart diseases, thyroid gland with hormonal dysfunction, cancer, kidney disease, kidney failure, encephalopathy, epilepsy, and other mental illnesses .

When used, capsular and tablet forms of Ribavirin cause serious side effects in patients, such as, for example, hemolytic anemia. Hemolysis is the main toxic effect of ribavirin. A decrease in hemoglobin levels of 20 g / l, 30 g / l and 40 g / l was observed in 31%, 27% and 23% of patients, respectively, who received combination therapy with ribavirin and interferon-alpha-2b for 48 weeks. Therefore, during treatment with Ribavirin, it is necessary to control the content of hemoglobin, bilirubin and uric acid.

Typical side effects are dyspnea, cough, sleep disturbances, exanthema. Less common are flu-like events with fever, headache and joint pain, weight loss, nausea, hair loss, and depression.

Thyroid dysfunction is rarely observed in the form of a change in TSH content, as well as allergic reactions (urticaria, bronchospasm, anaphylaxis). Thyroid dysfunction requiring therapeutic treatment was observed in 3% of cases. Symptoms of autoimmune diseases, arterial hypotension, leukopenia, thrombocytopenia are extremely rare. In most cases, anemia, leukopenia, neutropenia, granulocytopenia and thrombocytopenia were not very pronounced. All observed effects are reversible.

Currently, the attention of researchers and drug developers is attracted by more effective dosage forms, antiviral drugs obtained by liposome technology are being offered. Liposomes are microscopic spherical particles filled with liquid, their membrane (shell) consists of the molecules of the same natural phospholipids that are part of cell membranes, it is proved that liposomes are not toxic and completely biodegradable, that is, they are destroyed by ordinary enzymes present in blood flow.

The generally accepted standard regimen for the etiotropic treatment of chronic viral hepatitis C (HVHS), which provides for parenteral administration of recombinant alpha-interferon preparations in combination with other antiviral agents, has insufficient effectiveness and is associated with numerous side effects of the drugs and the inconvenience of prolonged parenteral use. The tasks are solved by a new method of treatment of chronic hepatitis, which consists in the appointment of the oral dosage form of the liposomal interferon drug Reaferon-EU-Lipint in combination with the injection of Reaferon-EC and the liposomal ribavirin Ribavirin-LIPINT.

The drug "Ribavirin-LIPINT"

The drug "Ribavirin-LIPINT" (registration certificate LP-000634 from 09/26/2011), manufacturer of CJSC Vector-Medica, Novosibirsk. The active substance - ribavirin is enclosed in a liposomal capsule.

Ribavirin, located in the liposome, is protected by its membrane from the effects of the internal environment of the body, and on the other hand, the same membrane does not allow the toxic drug to exceed the allowable concentration in body fluids. In this case, liposomes play the role of storage, from which the drug is released gradually, in the right doses and over the required period of time.

Liposomes protect ribavirin in the gastrointestinal tract to the point of absorption of all lipids (proximal part of the small intestine). The cholesterol, lecithin and vitamin E present in the preparation, in turn, have antioxidant and stabilizing effects on liposomes and ribavirin. It is known that finely emulsified fats (the size of fat droplets no more than 0.5 microns) are partially absorbed through the intestinal wall without prior hydrolysis. By its physicochemical nature, a liposome preparation is similar to emulsified fats. The average liposome size in the Ribavirin-LIPINT preparation is 0.25 μm, therefore, their partial absorption and interaction with the intestinal mucosa occurs without hydrolysis and, accordingly, without liposome degradation, which increases the therapeutic efficacy of ribavirin by oral administration and allows to reduce the dose, thereby reducing the toxicity of the drug.

Upon entry into the blood, liposomes are excreted from the bloodstream by macrophages, which deliver them to the liver, spleen and bone marrow (organs of the reticuloendothelial system). Rapid elimination of the drug "Ribavirin-LIPINT" from the blood can significantly reduce the hemolytic effect of ribavirin. The natural focus of macrophages on liposomes with ribavirin incorporated in them contributes to their activation, which is very useful for combating viral infections.

Liposomes are not retained by organs such as the heart, kidneys, brain, and cells of the nervous system, which makes it possible to significantly reduce cardiotoxicity, nephrotoxicity, and neurotoxicity by using the liposomal form of ribavirin. Thus, the liposomal form of ribavirin allows to obtain higher therapeutic efficacy and bioavailability of the drug, as well as reduce its toxicity, which was confirmed by the preclinical and clinical studies of Ribavirin-LIPINT. Preclinical trials of the drug Ribavirin-LIPINT were performed at the Russian Cardiology Research and Production Complex of the Ministry of Health of the Russian Federation Research Institute of Experimental Cardiology [Report on the preclinical toxicological study of the liposomal dosage form of ribavirin for oral administration (“Ribavirin liposomal”). Moscow. 2004, 24 pp.].

The toxicological study program included the study of the toxicity and tolerability of this dosage form for a single administration to laboratory animals, the study of its toxicity in a 1-month chronic experiment in dogs. In addition, a study was conducted of the allergenic properties of the drug.

Summing up the toxicological study of a new dosage form of ribavirin for oral administration of "Ribavirin-LIPINT" with various methods of single administration to laboratory animals, it can be noted that this dosage form of the drug is low toxic.

The toxicity study of Ribavirin-LIPINT in a chronic experiment was conducted on dogs with a daily 1-month administration of the drug in the finished dosage form at a dose of 133 mg / kg, which exceeded the highest daily dose for humans (1000 mg / person / day or 13 , 3 mg / kg / day) 10 times.

As the studies showed, “Ribavirin-LIPINT” in a tested dose of 133 mg / kg in a 1-month chronic experiment on dogs is well tolerated by animals and does not affect hematological parameters, the functional state of the main organs and systems of the animal’s body (according to the used biochemical tests and ECG). The absence of toxic damage to internal organs associated with the action of "Ribavirin-LIPINT" was confirmed by the results of pathomorphological studies conducted after the end of the chronic experiment. When studying the allergenic properties, it was found that with 5-fold intragastric administration to Guinea pigs “Ribavirin-LIPINT” in sensitizing doses of 66.5 and 13.3 mg / kg and with intragastric administration of a resolving dose of the drug (133 mg / kg) at 14 and 21 days after sensitization, Ribavirin-LIPINT does not cause anaphylactic shock.

"Ribavirin-LIPINT" in the tested doses and sensitization regimens does not show an allergenic effect in the delayed-type hypersensitivity reaction in guinea pigs and in the reaction of the popliteal lymph node in mice.

Thus, the new dosage form of ribavirin - "Ribavirin-LIPINT" is low toxic. In addition, in the course of an animal study, it was found that the bioavailability of ribavirin liposomal increases compared to ribavirin (C max and AUC increased by 70%), and due to this, a decrease in the therapeutic dose and, as a result, a decrease in side effects during treatment .

Description of a method for the treatment of chronic hepatitis C virus

The developed scheme of complex antiviral therapy using: ribavirin liposomal, Reaferon-EC-Lipint and Reaferon-EC was highly effective in the treatment of CVH C.

Suggested treatment regimen:

Ribavirin-LIPINT 1000 mg daily;

Reaferon-EU-Lipint 1 million ME 2 times a day (morning / evening), every other day;

Reaferon-EU 3 million IU intramuscularly, 3 times a week.

The course of treatment is 6 months.

The task solved by this technical improvement is to increase the effectiveness of treatment in the form of achieving clinical and laboratory remission by reducing the activity of the process in shorter periods of treatment, reducing the number of side effects of the therapy.

The mode of application of the method is selected on the basis of experimental and clinical observations given in example 1.

Example 1. Clinical study "Assessment of tolerability and therapeutic efficacy of liposomal drugs" Ribavirin-LIPINT "and" Reaferon-EU-Lipint "in the complex antiviral therapy in patients with chronic viral hepatitis C" was carried out on two clinical bases: clinical department of viral hepatitis (2- I am a clinical infectious diseases hospital of the Central Research Institute of Epidemiology of the Ministry of Health of the Russian Federation, Moscow) and LLC SPC Ozonoterapii (Moscow) [20].

The study involved 60 patients with chronic viral hepatitis C aged 18-50 years (average age 28.7 years).

The main treatment group received the developed treatment regimen: Ribavirin-LIPINT 1000 mg daily + Reaferon-EU-Lipint 1 million ME 2 times a day (morning / evening), every other day + Reaferon-EU 3 million ME , subcutaneously, 3 times a week.

The control group was treated according to the standard scheme: Ribavirin at a dose of 800-1000-1200 mg per day, depending on body weight + Reaferon-EU 3 million IU, subcutaneously, 3 times a week.

The study of the drug for chronic viral hepatitis C was carried out in groups of patients comparable in severity and severity of clinical and laboratory symptoms of the disease, as well as gender, age and body weight.

The criteria for inclusion of patients for participation in the clinical trial “Assessment of tolerability and therapeutic efficacy of liposomal drugs“ Ribavirin-LIPINT ”and“ Reaferon-EU-Lipint ”in complex antiviral therapy in patients with chronic viral hepatitis C” were:

1. Men and women aged 18-50 years.

2. Confirmation of the clinical diagnosis by the presence of HCV RNA in the blood, as determined by PCR and antibodies to hepatitis C virus, determined by ELISA.

3. The absence of severe fibrosis or cirrhosis of the liver according to clinical and laboratory data.

4. An increase in the activity of the enzyme alanine aminotransferase (ALT) by 1.5 times or more from the upper limit of the norm during screening or during the last month before starting therapy.

5. The absence over the past 6 months of antiviral therapy, the use of steroids, immunomodulators.

6. The duration of hepatitis C disease is more than 6 months.

7. Informed consent of the patient to participate in clinical trials.

8. Negative pregnancy test (for women).

The results of the studies indicate good tolerance of liposomal drugs: Reaferon-EU-Lipint and Ribavirin-LIPINT in patients with chronic hepatitis C. In the majority of patients, in the first month of treatment, the so-called side effects were observed that are characteristic of parenteral interferon therapy (see table No. 1).

Flu-like syndrome (fever, malaise, myalgia, arthralgia) was recorded with approximately the same frequency in the main and control groups: 86.7% and 90%, respectively. In later periods, other adverse reactions were observed with approximately the same frequency: decreased mood, hair loss, itchy skin, dyspepsia. It was noteworthy that in the experimental group, an increase in the total dose of interferon due to the inclusion of Reaferon-EU-Lipint in the treatment regimen did not entail an increase in pyrogenic and other reactions.

Table number 1 Adverse Event Data Side effects Patient Distribution (n /%) The main group (n = 30) Control group (n = 30) Number of patients % Number of patients % Flu-like sm 25 83.3% 27 90% Mood decline four 13.33% 2 10% Hair loss 2 6.67% four 13.33% Itchy skin, rash 5 16.67% four 13.33% Dyspepsia, abdominal pain 2 6.67% 2 6.67% Autoimmune manifestations - - one 3.34% Icteric syndrome four 13.33% 7 23.33% Leukopenia <3.5 thousand. 9 thirty% 10 33.33%

Jaundice syndrome, characterized by moderate yellowness of sclera and skin, an increase in indirect bilirubin, a decrease in hemoglobin and red blood cells, was recorded during treatment in 4 people (13.33%) of the main group and 7 (23.33%) of the control group.

Thus, although Ribavirin-LIPINT is capable of a higher concentration of the drug in the liver, its toxic effect was 1.75 times less than in the control group.

In the course of treatment, a number of patients revealed the toxic effect of drugs on pigment metabolism. Indirect hyperbilirubinemia was observed almost 2 times more often in patients of the control group (7 people, versus 4 in the experimental group), which was regarded as the hemotoxic effect of ribavirin due to hemolysis of red blood cells. In two patients of the main group and in 5 patients of control, the increase in total bilirubin reached 40.2 μmol / L, which required a short-term withdrawal of ribavirin. Subsequently, treatment was continued without repeated disturbance of pigment metabolism.

It was found that adverse reactions possible with ribavirin (jaundice, hyperbilirubinemia, decreased hemoglobin and red blood cells) were recorded in the experimental group almost 2 times less than in the control group.

When prescribing the developed treatment regimen, the incidence of side effects does not exceed similar indicators according to the literature and is slightly less than the standard treatment for hepatitis C. There is less hemotoxic effect of the drug Ribavirin-LIPINT, with the indicated treatment regimen, an increase in the total dose of interferon administered does not lead to an increase frequency of adverse reactions.

It was found that the proposed treatment regimen affects the effectiveness of the treatment of chronic hepatitis C.

In the overwhelming majority of patients of the main group receiving liposomal therapy according to the developed scheme, after 2-4 weeks they felt much better, increased working capacity, astheno-vegetative phenomena disappeared, the severity in the liver and spleen decreased, and the size of the liver and spleen normalized.

In 10.3% (3) patients asthenic events were recorded within 2 months of therapy. With standard treatment, asthenic events persisted in 27.5–8% (8 patients) for 3 months and in 3.7% (1) up to 6 months of follow-up. Pain and dyspeptic symptoms were stopped in 100% of cases by the end of 1 month of therapy in both observation groups.

It was found that hepatolienal syndrome normalized faster than with standard antiviral therapy. So, by the end of the first month in 26% of patients of the main group, the liver was palpated at the edge of the costal arch, while in the control group - only by the 3rd month of treatment.

Table number 2 The degree of decrease in ALT activity after 6 months of treatment in relation to the initial level Group The number of patients with different dynamics of ALT Reduction to normal More than 50% reduction Less than 50% reduction No dynamics or enhancement The main group (n = 28) n % n % n % n % 23 82.1 3 10.7 one 3,5 one 3,5 Control Group (n = 27) 19 70.3 3 11.1 3 11.1 3 11.1

Clinical improvement was characterized by a more pronounced regression of complaints and objective symptoms of chronic hepatitis C in patients of the main group.

Improving the effectiveness of treatment when prescribing the developed treatment regimen was also confirmed by achieving clinical and laboratory remission by reducing the activity of the process in a shorter treatment period, in comparison with standard treatment.

Table number 3 The level of ACT with different activity of CVHC in the dynamics of treatment Degree of activity Number of patients Fermentemia level (ACT norm up to 42 units / l) Before treatment In 2 weeks After 1 month 2 months later In 3 months In 6 months M + m M + m M + m M + m M + m M + m Low Main group 8 44.0 ± 5.3 28.2 ± 4.2 34.87 ± 6.0 27.6 ± 6.7 46.08 ± 9.6 42.8 ± 13.5 Control group fourteen 48.0 ± 6.7 42.2 ± 6.0 28.2 ± 8.9 29.1 ± 9.4 31.07 ± 11.2 35.0 ± 13.4 Moderate Main group eighteen 68.75 ± 12.5 43.75 ± 8.2 41.36 ± 9.0 28.7 ± 8.2 26.3 ± 7.6 38.3 ± 7.7 Control group 12 68.3 ± 25.6 57.2 ± 15.0 38.5 ± 12.4 36.2 ± 11.4 34.4 ± 15.6 33.6 ± 15.5 High Main group four 194.2 ± 53.4 76.4 ± 11.8 49.7 ± 10.3 49.8 ± 11.4 51.6 ± 11.6 42.3 ± 8.1 Control group four 170.75 ± 32.5 121.2 ± 26.4 98.7 ± 27.2 86.4 ± 21.9 73.7 ± 24.1 67.0 ± 5.8

Table number 4 The dynamics of viremia in patients with CVHC during treatment Observation period Patient groups The degree of hepatitis activity Total RNA + Low Moderate High Before treatment Main 8 (100%) 18 (100%) 4 (100%) 30 (100%) RNA + Control 14 (100%) 12 (100%) 4 (100%) 30 (100%) 2 months later Main 2 (25%) 3 (16.7%) 1 (33.3%) 6 (20%) RNA + Control 3 (21.4%) 4 (33.3%) 3 (75%) 10 (33.3%) After 4 months Main 2 (25%) 3 (16.7%) 0 5 (17.2%) RNA + Control 6 (46.2%) 4 (33.3%) 1 (50%) 11 (37.9%) After 6 month Main 1 (12.5%) 3 (16.7%) 0 4 (14.29%) RNA + Control 6 (50%) 4 (33.3%) 1 (50%) 11 (40.74%)

A comparison of the data on fermentemia before treatment and after treatment indicates a more pronounced biochemical effect in the main group. Significant positive biochemical effect (i.e., reduction to normal or by more than 50%) by the end of the observation period was observed in 92.8% of patients of the main group and 81.4% of the control group (tables 2 and 3).

The most pronounced effect of antiviral therapy on the virologic response to HCV RNA was detected in the experimental group of patients.

So, after 2 months of treatment in this group, the virus in the blood was detected 1.7 times less than in the control. By 6 months of treatment, the virus was detected in only 4 people, of which 2 people with genotype 1b, 1 with genotype 1a and 1 person with genotype 3a. In the control group, at 6 months, viremia persisted in 11 people, including 7 people with genotype 1c and 4 people with genotype 3a (tables 4 and 5).

After 6 months of therapy, a complete virological response was obtained in 85.7% of patients in the main group and 59.3% of patients in the control group, that is, the effectiveness of the proposed treatment regimen is 26.4% more with standard treatment.

Thus, the developed scheme of complex antiviral therapy using: Ribavirin-LIPINT, Reaferon-EU-Lipint and Reaferon-EC was highly effective in the treatment of HCV.

Table number 5 Virological response in patients with chronic hepatitis C to HCV versus HCV genotype Observation period groups Virus genotype 1c 2a 3a 1a one 11 pax 2 pax 16 pax 1 pax Before RNA + treatment 2 12 pax 1 pax 15 people 2 pax 2 months one 3 pax 2 pax 1 pax RNA + 2 6 people 4 pax 4 months one 2 pax 2 pax 1 pax RNA + 2 8 pax 3 pax 6 months one 2 pax 1 pax 1 pax RNA + 2 7 pax 4 pax

Claims (2)

1. A method of treating chronic viral hepatitis C with liposomal form preparations, comprising oral administration of liposomal preparations of alpha-2 interferon and ribavirin to the body, characterized in that it includes the additional administration of an injectable form of alpha-2 interferon in the form of “Reaferon-EC” at a dose of 3 million ME, subcutaneously, 3 times a week, “Reaferon-EC-Lipint” is used as the liposomal preparation of alpha-2 interferon, and “Ribavirin-LIPINT” is used as the liposomal preparation of ribavirin, which are administered with follows: "Ribavirin-LIPINT" 1000 mg daily and "IFN-EU Lipint" 1 million ME 2 times a day, morning and evening every other day during the course of treatment, ensures the achievement of clinical and laboratory remission.. 2. The method according to claim 1, characterized in that the course of treatment with liposome preparations and the injectable form of alpha-2 interferon "Reaferon-EC" is 6 months.