RU2212248C1 - Method for treating patients for viral hepatitis c - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves intramuscularly administering rheaferon before cycloferon being taken, at a dose of 3 mln of MU 3 times a week during 18-20 days. Cycloferon treatment course is to be prolonged to 7-9 weeks ones per 5 days at a dose of 600 mg. 2-4 courses of combined rheaferon and cycloferon therapy are carried out on the background of vitamins B group and hepatoprotector agents consumption. EFFECT: enhanced effectiveness of treatment; improved clinical, biochemical and virusological parameters. 2 tbl

Description

 The invention relates to medicine, in particular to internal medicine, and for the treatment of patients with chronic viral hepatitis C (HVHS).

 A known method of treating patients with chronic hepatitis C with recombinant α-interferon (α-IFN) - Intron A, which has both a direct antiviral effect and mediated immunomodulating activity. The dose of Intron A was 3 million ME 3 times a week for 6 months (Mc Hutchison J., Gordon S., Schiff E. et al. Or in combination witn ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N. Engl. J. Med. 1998, 339: 1485-1492). At the same time, the low efficacy of α-interferon monotherapy was proven in patients with chronic hepatitis C: the response rate did not exceed 6% with treatment for 6 months. and 13% - within 12 months. The effectiveness of HCV monotherapy caused by the virus 1b genotype, which is quite common in Russia, is even lower and amounts to only 2-7%.

 A known method for the treatment of patients with chronic hepatitis C using the treatment regimen of IFN-α 6 million ME 3 times a week for 4 months and then 3 million ME 3 times a week for 8 months (Chemelto L., Bonetti P., Cavalletto L. et al Hepatology. -1995. - 22. - p. 700-706). In this case, a long-term response was recorded in 49% of patients with chronic hepatitis C. However, the side effects of interferon therapy significantly limit their use. The first dose of interferon usually causes a flu-like syndrome, lasting no more than 12 hours in 72% of patients with HCV. The severity of fever, chills, arthralgia, myalgia, headache, fatigue decreases with repeated use, although fever and myalgia can persist. Other serious side effects (gastrointestinal and psychiatric symptoms, myelosuppression, thyroid dysfunction) that occur with the regular use of interferon in 10-25% of patients with chronic hepatitis C complicate treatment. In addition, exogenously administered interferon in 42% of patients with chronic hepatitis C causes the production of autoantibodies, which, according to some authors, affects the decrease in the effectiveness of the therapy.

 As a prototype for the achieved antiviral effect, we have chosen a method for treating CVHC with cycloferon tablets in a daily dose of 600 mg. once, 30 minutes before meals, on 1, 2, 4, 6, 8, 11, 14, 17, 20, 23, 26, 29 days (48 tablets in total) (Sologub T.V., Nevzorva T.G., Grigoryeva TD Viral hepatitis B and C: clinic, diagnosis, treatment. AquaVitae 2000, 2, 9-16). Cycloferon is an inducer of interferons, a drug of the acridine series, developed by Polisan Scientific and Production Center, has a mild, prolonged immunocorrective effect. It is produced in ampoules of 2 ml of a 12.5% solution, administered intramuscularly or intravenously, and in tablets of 150 mg. Cycloferon promotes the formation in the body of leukocytes, macrophages, fibroblasts, epithelial cells of α-, β- and γ-interferons, has an immunomodulatory effect. Inducing the active synthesis of interferons using their inducers is an alternative approach to the treatment of patients with chronic hepatitis C. Interferon inducers have several significant advantages over IFN drugs: endogenous IFN produced in response to the introduction of interferonogens does not have antigenicity, its synthesis in the body is balanced and undergoes regulatory and regulatory mechanisms that protect the body from oversaturation (Ershov F.I., Golubev S .U., Kovalenko A.L. et al. Antiviral agents. / Under the editorship of M. Romantsov - St. Petersburg, 1996).

 However, the appointment of IFN inducers in the treatment of chronic hepatitis with severe depression of the IFN system does not always entail a positive clinical effect. This is because the effect of IFN inductors in this situation is not able to provide the production of a sufficient amount of IFN, since the system is not able to respond to the inducing effect. In such cases, the appointment of IFN inducers is not a justifiable measure (V. Radchenko, A. V. Shabrov and other Chronic liver diseases. - St. Petersburg, 2000) and will not lead to the desired results. For chronic viral infections (herpes, hepatitis B), as well as a number of diseases of a non-viral nature, a marked suppression of interferonogenesis is characteristic. Moreover, interferon production is more significantly suppressed in patients with severe chronic disease. Background indicators of serum interferon are combined with the sharply inhibited ability of immunocytes to synthesize interferon-α, interferon-γ (Isakov V.A., Borisova V.V. et al. Herpes. Pathogenesis and laboratory diagnostics. - St. Petersburg, 1999).

 The objective of the invention is to develop a method of treating patients with chronic hepatitis C, increasing the effectiveness of the treatment by improving clinical, biochemical, virological parameters.

 The problem is solved in that the patient after a preliminary assessment of IFN status; while taking B vitamins, hepatoprotectors and cycloferon, in addition to taking cycloferon, reaferon (interferon-α2b, Vector Pharm, Russia) is prescribed intramuscularly at a dose of 3 million ME 3 times a week for 18-20 days, and the course of treatment with cycloferon extend to 7-9 weeks with a frequency of taking cycloferon, 1 time in 5 days at a dose of 600 mg, and from 2 to 4 courses of combination therapy with reaferon and cycloferon are carried out.

 The method is as follows.

 The method does not require special preparation of the patient. The patient, while taking B vitamins, hepatoprotectors and cycloferon, is additionally prescribed reaferon intramuscularly at a dose of 3 million ME 3 times a week for 18-20 days before taking cycloferon, and the course of treatment with cycloferon is extended to 7-9 weeks with a frequency of cycloferon administration, 1 time in 5 days at a dose of 600 mg, and from 2 to 4 courses of combination therapy with reaferon and cycloferon are carried out.

 A distinctive feature of the proposed method is the appointment of reaferon (interferon-α2b "Vector Farm", Russia) intramuscularly at a dose of 3 million ME 3 times a week for 18-20 days before taking cycloferon and prolonging the course of cycloferon to 7-9 weeks with a frequency of taking cycloferon , 1 time in 5 days at a dose of 600 mg. According to our data, in patients with chronic hepatitis C, a significant imbalance in the interferon system is observed: the inhibition of interferonogenesis is greater, the more pronounced the activity and the greater the stage of fibrosis of chronic hepatitis. In patients with this nosology with severe depression of the IFN system, the appointment of monotherapy with cycloferon, as an interferon inducer, is not capable of achieving positive clinical results. This is because the effect of IFN inductors in this situation is not able to provide the production of a sufficient amount of IFN, since the system is not able to respond to the inducing effect. Based on this, it seems to us appropriate for patients with chronic hepatitis C to have established IFN deficiency to undergo substitution therapy with IFN-α drugs before the appointment of IFN inducers, in particular cycloferon.

 The presented method of treatment was applied in 20 patients with chronic hepatitis C. Extracts from medical histories are given as an example.

 Example 1

 Medical history 13802.

 Patient I., 40 years old.

 Diagnosis: chronic viral hepatitis C, with severe activity, grade 3 fibrosis.

 Concomitant: peptic ulcer of the duodenum, without exacerbation.

 At admission, he complained of weakness, decreased performance, pain in the right hypochondrium, unstable chair.

 Sick for 7 years. Periodically took hepatoprotectors.

Objective upon admission: the condition is satisfactory, the skin is clean, normal color, sclera subicteric. Pulse 76 beats / min, rhythmic. HELL 130/70 mm RT. Art. Heart sounds are clear, rhythmic, the ratio of tones is not changed. The liver is enlarged, protrudes from under the edge of the costal arch by 2.5 cm, the spleen is not palpable. During the examination: red blood cells 4.36 • 10 ¹² / l, hemoglobin 132 g / l, color index 0.92, white blood cells 6.0 • 10 ⁹ / l, platelets 143.8 • 10 ⁹ / l, ESR 2 mm / h , AcAT 0.38 mmol / L, AlAT 2.08 mmol / L, bilirubin 7.2 μmol / L, alkaline phosphatase 83 U / L, GGTP 65 U / L, thymol sample 5.5 ALL, albumin - 54%, gamma -globulins - 24.5%. Indicators of interferon status: serum interferon 26 ME, induced production of IFN-α / β 72 ME, induced production of IFN-γ 32 ME, PCR-HCV in the blood serum is positive.

 In a morphological study of the liver: lobular architectonics preserved, granular, hydropic and fatty degeneration of hepatocytes, moderate nuclear polymorphism. Focal and step necrosis of hepatocytes. Severe lymphoid infiltration of the portal tracts. Portal tracts are moderately expanded, fibrosed with the onset of septic formation. Moderate lymphoid sinusoid infiltration. The index of histological activity (IGA, Knodell) 8 points, fibrosis 2 degrees.

 Treatment: along with the parenteral administration of riboxin, B vitamins, essentials and cycloferon, the patient was additionally given intramuscular reaferon at a dose of 3 million ME 3 times a week for 18 days before taking cycloferon, the course of treatment with cycloferon was extended up to 7 weeks with a frequency of taking cycloferon, 1 every 5 days at a dose of 600 mg, and the patient received 2 of these courses of combination therapy with reaferon and cycloferon. After the treatment, the patient's condition improved: the manifestations of asthenovegetative syndrome disappeared, the pain syndrome in the right hypochondrium was leveled, and the size of the liver decreased.

During the examination: red blood cells 4.98 • 10 ¹² / l, hemoglobin 130 g / l, color index 0.79, white blood cells 4.28 • 10 ⁹ / l, platelets 278 • 10 ⁹ / l, ESR 2 mm / h, AsAT 0.13 mmol / l, AlAT 0.66 mmol / l, bilirubin 10 μmol / l, alkaline phosphatase 83 U / l, GGTP 45.3 U / l, thymol sample 2.5 ALL, albumin - 61%, gamma globulins - 16%. Indicators of interferon status: serum interferon 16 ME, induced production of IFN-α / β 196 ME, induced production of IFN-γ 82 ME, PCR-HCV serum negative.

 In a morphological study of the liver: lobular architectonics preserved, a decrease in the manifestations of granular and hydropic degeneration of hepatocytes. Significant decrease in the severity of lymphoid infiltration of portal tracts, sinusoids: IGA 5 points, fibrosis 2 degrees.

 Example 2

 Medical history 15427.

 Patient K., 18 years old.

 Diagnosis: chronic viral hepatitis C, with severe activity, grade 2 fibrosis.

 Concomitant: chronic gastroduodenitis, without exacerbation, bilateral nephroptosis with impaired urodynamics.

 At admission complained of an asthenovegetative nature, dyspeptic syndrome.

 Sick for 2 years. Not treated.

Objective upon admission: the condition is satisfactory, the skin is clean, normal color, sclera subicteric. Pulse 78 beats / min, rhythmic. HELL 130/80 mm Hg Heart sounds are clear, rhythmic, the ratio of tones is not changed. The liver is enlarged, protrudes from the edge of the costal arch by 2 cm, the spleen is not palpable. During the examination: red blood cells 4.17 • 10 ¹² / l, hemoglobin 124 g / l, color index 0.9, leukocytes 3.7 • 10 ⁹ / l, platelets 166.8 • 10 ⁹ / l, ESR 3 mm / h , AcAT 0.65 mmol / L, AlAT 2.36 mmol / L, bilirubin 30 μmol / L, alkaline phosphatase 98 U / L, GGTP 30.4 U / L, thymol sample 3.0 ALL, albumin - 36.6% , gamma globulins - 36.3%. Indicators of interferon status: serum interferon 25 ME, induced production of IFN-α / β 78 ME, induced production of IFN-γ 52 ME, PCR-HCV serum positive.

 In a morphological study of the liver: lobular architectonics preserved, granular and hydropic dystrophy of hepatocytes, some of them are of a sand type, and in some places polymorphism of nuclei. Portal tracts are moderately expanded, fibrosed with dense lymphomacrophagic infiltration, with the onset of septic formation. Histological activity index (IHA, Knodell) 15 points, fibrosis 2 degrees.

 Treatment: along with the parenteral administration of riboxin, B vitamins, essentials and cycloferon, the patient was additionally prescribed intramuscularly reaferon at a dose of 3 million ME 3 times a week for 20 days before taking cycloferon, the course of treatment with cycloferon was extended up to 8 weeks with a frequency of taking cycloferon, 1 every 5 days at a dose of 600 mg, and the patient received 3 of the above courses of combination therapy with reaferon and cycloferon. After the therapy, the patient's condition improved: the manifestations of the asthenovegetative syndrome disappeared, and the size of the liver decreased.

During the examination: red blood cells 4.09 • 10 ¹² / l, hemoglobin 120 g / l, color index 0.9, white blood cells 4.5 • 10 ⁹ / l, platelets 245.4 • 10 ⁹ / l, ESR 2 mm / h , AcAT 0.46 mmol / L, AlAT 0.59 mmol / L, bilirubin 13 μmol / L, alkaline phosphatase 65 U / L, GGTP 29.6 U / L, thymol sample 1 ALL, albumin - 56%, gamma globulins - 16%. Indicators of interferon status: serum interferon 20 ME, induced production of IFN-α / β 156 ME, induced production of IFN-γ 74 ME, PCR-HCV serum negative.

 In a morphological study of the liver: lobular architectonics preserved, a decrease in the manifestations of granular and hydropic degeneration of hepatocytes. Reduction of lymphomacrophagal portal tract infiltration: IGA 8 points. Fibrosis 2 degrees.

 Example 3

 Medical history 6192.

 Patient X., 21 years old.

 Diagnosis: chronic viral hepatitis C, with severe activity, grade 3 fibrosis.

 Concomitant: chronic gastroduodenitis, without exacerbation, bilateral nephroptosis, chronic pyelonephritis, without exacerbation; secondary arterial hypertension.

 At admission complained of an asthenovegetative nature, dyspeptic syndrome.

 Sick for about 2 years. Not treated.

Objective upon admission: the condition is satisfactory, the skin is clean, normal color, sclera subicteric. Pulse 68 beats / min, rhythmic. HELL 140/90 mm Hg Heart sounds are clear, rhythmic, the ratio of tones is not changed. The liver is enlarged, protrudes from the edge of the costal arch by 3 cm, the spleen is not palpable. During the examination: red blood cells 4.18 • 10 ¹² / l, hemoglobin 126 g / l, color index 0.92, white blood cells 5.4 • 10 ⁹ / l, platelets 213.18 • 10 ⁹ / l, ESR 1 mm / h , AcAT 1.25 mmol / L, AlAT 4.0 mmol / L, bilirubin 10 μmol / L, alkaline phosphatase 118 U / L, GGTP 25.3 U / L, thymol sample 10.5 ALL, albumin - 45.2% , gamma globulins - 26.3%. Indicators of interferon status: serum interferon 29 ME, induced production of IFN-α / β 58 ME, induced production of IFN-γ 40 ME, PCR-HCV serum positive.

 In a morphological study of the liver: lobular architectonics preserved, granular and hydropic degeneration of hepatocytes, pronounced polymorphism of the nuclei. Common focal, step and bridge necrosis of the port-portal and port-central. Severe lymphoid sinusoid infiltration. Portal tracts are sharply expanded, fibrosed with dense lymphomacrophagic infiltration, with an admixture of plasma cells, with the onset of septic formation. Histological activity index (IHA, Knodell) 18 points, fibrosis 3 degrees.

 Treatment: along with the parenteral administration of riboxin, B vitamins, essentials and cycloferon, the patient was additionally given intramuscularly reaferon at a dose of 3 million ME 3 times a week for 21 days before taking cycloferon, the course of treatment with cycloferon was extended up to 9 weeks with a frequency of cycloferon, 1 every 5 days at a dose of 600 mg, and the patient received 4 of the above courses of combination therapy with reaferon and cycloferon. After the therapy, the patient's condition improved: the manifestations of the asthenovegetative syndrome disappeared, and the size of the liver decreased.

During the examination: red blood cells 4.23 • 10 ¹² / l, hemoglobin 128 g / l, color index 0.91, white blood cells 5.8 • 10 ⁹ / l, platelets 194.5 • 10 ⁹ / l, ESR 3 mm / h , AcAT 0.33 mmol / L, AlAT 0.46 mmol / L, bilirubin 13 μmol / L, alkaline phosphatase 121 U / l, GGTP 35.7 U / l, thymol sample 5.0 ALL, albumin - 53.6% , gamma globulins - 18%. Indicators of interferon status: serum interferon 16 ME, induced production of IFN-α / β 139 ME, induced production of IFN-γ 95 ME, PCR-HCV serum negative.

 In a morphological study of the liver: lobular architectonics preserved, a decrease in the manifestations of granular and hydropic degeneration of hepatocytes. Significant decrease in the severity of lymphomacrophagous infiltration of portal tracts: IGA 9 points, fibrosis 3 degrees.

 Test case.

 Medical history 17958.

 Patient E., 42 years old.

 Diagnosis: chronic viral hepatitis C with a moderate degree of activity, grade 3 fibrosis.

 Concomitant: chronic gastroduodenitis, without exacerbation; gallstone disease, chronic calculous cholecystitis.

 At admission he complained of weakness, decreased performance, pulling pains in the right hypochondrium, weight loss.

 Sick for about 8 years. Periodically took hepatoprotectors.

Objective upon admission: the condition is satisfactory, the skin is clean, normal color, sclera subicteric. Pulse 67 beats / min, rhythmic. HELL 130/80 mmHg Heart sounds are clear, rhythmic, the ratio of tones is not changed. The liver is enlarged, protrudes from the edge of the costal arch by 3 cm, the spleen is not palpable. During the examination: red blood cells 3.1 • 10 ¹² / l, hemoglobin 110 g / l, color indicator 1.0, white blood cells 3.8 • 10 ⁹ / l, platelets 144 • 10 ⁹ / l, ESR 4 mm / h, AsAT 0.26 mmol / l, AlAT 1.3 mmol / l, bilirubin 21 μmol / l, alkaline phosphatase 91 IU / l, GGTP 121 IU / l, thymol sample 6.5 ALL, albumin - 48%, gamma globulins - 23 ,5%. Indices of interferon status: serum interferon 23 ME, induced production of IFN-α / β 140 ME, induced production of IFN-γ 54 ME, PCR-HCV serum positive.

 In a morphological study of the liver: lobular architectonics preserved, granular, hydropic and fatty degeneration of hepatocytes, moderate nuclear polymorphism. Focal necrosis of hepatocytes. Moderate lymphoid portal tract infiltration. Portal tracts expanded, the formation of septa. Moderate lymphoid sinusoid infiltration. IGA, Knodell 5 points, fibrosis 3 degrees.

 Treatment: along with the parenteral administration of riboxin, B vitamins, essentials, the patient was prescribed 2 twelve-week courses of cycloferon monotherapy: the first 29 days, cycloferon was administered orally in tablets in a daily dose of 600 mg once, 30 minutes before meals at 1, 2, 4, 6, 8, 11, 14, 17, 20, 23, 26, 29 days (48 tablets in total), then once every 5 days, 600 mg each. After the treatment, the patient's condition improved slightly: the manifestations of asthenovegetative syndrome decreased, the pain syndrome in the right hypochondrium remained.

During the examination: red blood cells 4.09 • 10 ¹² / l, hemoglobin 110 g / l, white blood cells 3.7 • 10 ⁹ / l, platelets 102 • 10 ⁹ / l, ESR 5 mm / h, AcAT 0.39 mmol / l , AlAT 0.78 mmol / L, bilirubin 18 μmol / L, alkaline phosphatase 97 U / L, GGTP 122 U / L, thymol sample 6.5 ALL, albumin - 52.3%, gamma globulins - 19%. Indicators of interferon status: serum interferon 26 ME, induced production of IFN-α / β 88 ME, induced production of IFN-γ 20 ME, PCR-HCV serum positive.

 Morphological examination of the liver: marked activity: hepatocyte balloon dystrophy, hepatocyte group necrosis, intense lymphohistiocytic infiltration in portal tracts and border plates. An increase in IGA to 10 points, fibrosis of 3 degrees.

 The inventive method of treatment was used in 20 patients with chronic viral hepatitis C. Of these, men accounted for 66.5%, women - 33.5%. The average age of patients: 28 ± 9 years.

 The comparison group consisted of 15 patients with chronic hepatitis C, comparable in sex and age, severity of activity and stage of fibrosis in the liver, treated with cycloferon monotherapy.

 The diagnosis was verified virologically: patients were determined anti-HCV-AB, RNA-HCV in serum by polymerase chain reaction, morphological examination of the liver by Mangini. The dynamics evaluated: biochemical blood parameters, clinical blood count, indicators of interferon status (serum interferon (IFN), induced production of IFN-α / β, IFN-γ).

 According to the claimed method, presented in table 1, after the initial course of antiviral therapy in patients with chronic hepatitis C, there was a decrease in serum interferon (s-IFN), a further increase in the induced production of IFN-α / β, IFN-γ; a decrease in the manifestations of cytolytic, mesenchymal-inflammatory syndromes, while in the prototype method low rates of induced production of IFN-α / β, IFN-γ were maintained. Data on the prototype are presented in table 2.

 The extracts from the case histories show that using the proposed method, it is possible to treat patients with HVGS more efficiently than the prototype by correcting the existing inhibition of the IFN system by IFN drugs with further induction of endogenous IFN by cycloferon.

 The inventive method improves the clinical, biochemical and virological parameters of patients with chronic viral hepatitis C. The primary biochemical and virological response according to the claimed method was 58%, and according to the prototype method 36%. A decrease in the histological activity index (IHA, Knodell) by the present method was observed from 15.3 to 8.2 points (p <0.001).

Claims (1)

 A method of treating chronic viral hepatitis C by prescribing a patient with B vitamins, hepatoprotectors and cycloferon, characterized in that, in addition to taking cycloferon, the patient is prescribed reaferon intramuscularly at a dose of 3 million ME 3 times a week for 18-20 days, and the course of treatment with cycloferon is prolonged up to 7-9 weeks with a frequency of taking cycloferon once every 5 days at a dose of 600 mg, and from 2 to 4 courses of combination therapy with reaferon and cycloferon are carried out.

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