Method for predicting the results of treating patients with chronic hepatitis c with interferon-alpha preparations

FIELD: medicine, gastroenterology.

SUBSTANCE: one should detect the synthesis of IFN-γ and IL-4 with mononuclears of peripheral blood in vitro before and 4.5 h after introducing the first dosage of interferon-α preparation. At detecting more that 2-fold increase of the synthesis of IFN-γ and the ratio of IFN-γ/IL-4 synthesis after the first introduction of interferon-α preparation for the patients with CVH C it is possible to predict the development of virological response in the course of 24-wk interferonotherapy. In case of increased synthesis of IFN-γ and the ratio of IFN-γ/IL-4 synthesis after the first introduction of interferon-α being less than 2-fold - the development of virological response should not be expected. Application of the present innovation enables to predict the results of therapy in shorter terms after the first introduction of interferon-α preparation.

EFFECT: higher accuracy of prediction.

2 ex, 1 tbl

 

The invention relates to medicine, namely to a gastroenterologist.

Predicting the effectiveness of treatment of patients with chronic viral hepatitis (hug) represents an important practical problem in connection with the high cost of antiviral drugs with numerous side effects when they are applied, as well as lack of ability to reliably eliminate virus from the patient's body and connected with this fact the need of the choice treatment techniques, including the use of pegylated interferons or ways of combination pharmacotherapy[1, 2, 3, 4].

Reliable methods for predicting a positive response to interferon therapy of chronic hepatitis C are missing. Using existing techniques can give very approximate prognostic evaluation. Among the predictors of good response to interferon therapy in patients with chronic viral hepatitis C include the following[5, 6, 7]:

low titer of HCV RNA before treatment;

- aminotransferases (not more than 2-3 norms);

- short duration of infection;

- ulterior fibrosis;

- the absence of cholestasis;

- the normal level of iron in serum and liver tissue;

2 and 3 HCV genotypes.

Most often as a prognostic signs of a favorable response to standard the reduction therapy hug With, including interferon therapy, called the genotype of the virus-1b and low viral load, and the combination of these features[8, 9, 10].

Among the predictors of poor response to interferon therapy for chronic viral hepatitis treated With such indicators as high levels of viremia, the presence of HCV mutants, HCV genotype 1 (especially 1b), and male gender, advanced age, prolonged infection, presence of cirrhosis, granules of iron in the liver, cholestasis syndrome.

The criteria of the forecast have several disadvantages:

1. The high cost of some methods, in particular for determining the titer of HCV RNA.

2. The need to use when determining the genotype and HCV RNA specialized and very expensive equipment (for PCR-analysis).

3. The ability of viral load to spontaneous fluctuations.

4. The impossibility of predicting the effectiveness of treatment in patients with non-genotype 1b virus, in which the outcome may be different.

Other prognostic methods of response to interferon therapy also have disadvantages: it is often impossible to determine the duration of infection, the difficulty of assessing the severity of fibrosis, the need to use invasive method of diagnosis is a biopsy of the liver, conduct additional who's research to assess the homogeneity of a population of HCV and the lack of mutants. None of the suggested methods of forecasting does not take into account individual patient response to antiviral drug.

The problem of development available for practical health care institutions predictor, increasing the accuracy of predicting treatment outcomes (in particular, the development of early virologic response in patients with chronic hepatitis C interferon-α.

The essence of the method lies in the fact that in mononuclear cells of peripheral blood collected before and after the first introduction of patient drug interferon-α in therapeutic doses, determine the synthesis of inflammatory mediators - IFN-γ and IL-4 and their relationship.

The method is as follows.

The criterion for inclusion is the availability of proven chronic hepatitis C (viral markers, including HCV RNA, genotype of the virus, histology of liver biopsy, the activity of Alt).

Exclusion criteria: concomitant pathology (acute or chronic diseases in the acute stage), the medication within 2 weeks prior to the survey, alcohol consumption, infection with the hepatitis b virus, HIV-infection.

The sampling of venous blood in patients spend in the morning, on an empty stomach and after 4.5 hours after the first injection of the drug interfer is on ("peak" therapeutic activity). Mononuclear cells release on the density gradient of ficoll-urografin according to the method of Ferrante And & Thoung Y.H. [11], the obtained cell population standardize (2×106cells in 1 ml) and incubated for 24 hours in culture medium RPMI-1640 with the addition of L-glutamine, 2% fetal calf serum and gentamicin in moist, rich CO2the atmosphere at 37°C. the Content of cytokines in supernatant, after centrifugation determined by ELISA using test kits: IL-4 - "Protein contour and IFN-γ "Cytokine".

Identify more than a twofold increase in the synthesis of IFN-γ and the ratio of synthesis of IFN-γ/IL-4 after the first injection the patient hug With interferon-α we can expect the development of virologic response during the 24-week interferonoterapii. In the case of increasing the synthesis of IFN-γ and the ratio of synthesis of IFN-γ/IL-4 after the first injection of interferon-α less than 2 times the formation of a virological response is not expected.

During the development of the method was examined patients hug C. After the survey was administered antiviral treatment with recombinant interferon-α (intron a - "Schering-Plough" or IFN - Vector) in a daily dose of 3 million ME 3 times a week for a period of 24 weeks (6 months). At the end of interferonoterapii conducted analysis of the results laciniata following results: HCV RNA in the blood, transaminases, gamma-glutamyltransferase, alkaline phosphatase, the content of bilirubin, thymol turbidity of the sample. With regard to testing HCV RNA patients were divided into 2 groups: group responders (responders) with the formation of early virologic response - the disappearance of HCV RNA, normalization of Alt and the group of "non-responders" (non-responders only) biochemical response - the preservation of HCV RNA and normalization or decrease of activity of Alat. Conducted a retrospective analysis to assess baseline synthesis by mononuclear cells from IFN-γ, IL-4, the ratio of IFN-γ/IL-4, as well as their dynamics during the first introduction of patient drug interferon-αwhose data were compared with the results of 24-week treatment of patients hug With interferon-α.

Results

In the group of 15 patients hug C with the presence of virological response at 24 weeks of interferon therapy (responders) were studied before treatment the synthesis of IFN-γ after the first administration to patients of interferon-α increased more than 2 times with 10,91±2,32 PG/2×106cells to 23,92±to 4.52 PG/2×106cells. The ratio of the original synthesis OLS IFN-γ/IL-4 on the background of the first administration to patients jug With 3 million MB of interferon-α rose 0.42±of 0.01 to 1.01±0,02 - i.e. more than 2 times.

In the group of the 10 patients with hug With no virological response with preservation of HCV RNA after treatment (non-responders) synthesis of IFN-γ after the first injection of interferon-α at a dose of 3 million increased from ME 10,14±2,07 PG/2×106cells to 17,32±to 2.65 PG/2×106cells, i.e. less than 2 times (average 70.6%). The ratio of the spontaneous synthesis of blood cells IFN-γ IL-4 after the first injection of interferon-α future non-responders increased from 0.45±0,015 to 0.61±0.03 to less than 2 times (on average 35.5%).

At the same time, patients from both comparison groups, there were no differences in baseline measurements of activity of aminotransferases, alkaline phosphatase, serum iron level, duration of HCV infection and morphological severity of fibrosis on a scale V.J. Desmet [12], as well as the percentage of patients with genotype 1b virus.

Table

Synthesis of cytokines by mononuclear cells of patients with chronic hepatitis C before and after the first injection of interferon-α depending on the results of 24-week interferonoterapii
The studied parameterThe group surveyed
respondersNon-responders
Spontaneous synthesis of IFN-γ (PG/2×106CL)

before the first introduction the Oia interferon-α < / br>
after the first injection of interferon-α


10.91±2.32< / br>
23,92±to 4.52


10,14±2.07< / br>
17,32±2,65
The ratio of IFN-γ/IL-4

prior to the first injection of interferon-α

after the first injection of interferon-α


0.42±0.01< / br>
1,01±0,02


0.45±0.015< / br>
0,61±0,03

From the presented data it follows that early virologic response to monotherapy with interferon-α patients with chronic hepatitis C should be expected if the increase in spontaneous synthesis of mononuclear cells IFN-γ and increase in the ratio of spontaneous synthesis of IFN-γ IL-4 (IFN-γ/IL-4) after the first introduction of patient drug interferon-α will more than double.

Clinical examples

Example 1. L.-S., 47, clerk, case history No. 6122. Was hospitalized in the gastroenterology Department with KKB 30.11.99 on 10.12.99,

Diagnosis. Chronic viral hepatitis C (HCV RNA +) with the least pronounced activity.

Upon receipt complained of General weakness, fatigue, joint pain, periodic, heaviness in the right hypochondrium. Ill for about 2 years.

Objectively. The condition is satisfactory. Skin on the cows and mucous regular color. The rhythmic heart sounds, pulse rate 80 in 1 minute. HELL 130/95 mm Hg Breathing above the light vesicular. The abdomen is soft, moderately painful palpation in the right upper quadrant. The liver acts from under the costal arch 1 cm, moderate density, painless. The size of her karlovu 13×10×8 see Spleen not palpated.

General blood and urine tests without deviation from the norm. Bilirubin is 22.2 mmol/L. Alt 70 U/l, AST 56 U/l, GGT 71 U/l, alkaline phosphatase 238 U/L. PETIT 98%. Total protein 80 g/l, albumin 56%, globulins: α-12%, β-11%, γ-21%. Blood glucose 3.6 mmol/l Thymol test 4,1% Ferritin 175,66 ng/ml CEC 90 UE (rule 70). Cholesterol 6.4 mmol/L.

Viral markers: aHCV +, aHCV IgM +, HCV RNA +. Markers of HBV infection, HIV negative.

Ultrasonography. Liver: right lobe 127 mm, parenchyma diffuse heterogeneous echogenicity increased. Intrahepatic ducts are not expanded. Portal vein 12 mm, splenic - 6 mm Choledoch 4 mm Gall bladder 82×32 mm, 3 mm wall, content homogeneous. Pancreas: head of 16 mm, the body is 15 mm, the tail is 17 mm, the tissue is homogeneous, moderately hyperechoic. Spleen 108×50 mm

Liver biopsy. Lobular structure saved. Portal tracts expanded with poor lymphomacrophagal infiltration, formation of isolated lymphoid follicles. Cellular infiltration in some areas penetrates beyond the edge of the plate OBR is using a single step of necrosis. Lobular component - a single small cell clusters in the territory of 1-2 hepatocytes, focal activation of reticulocytes and hyperplasia of hepatocytes.

Conclusion. Chronic hepatitis with mild activity. YOKE 4 points. Index Desmet 1 point.

Started treatment with interferon-α, (intron a) in the standard dose of 3 million ME 3 times a week. Tolerability was satisfactory workability saved. 3 months gone viremia (HCV RNA), however, the level of Alt was slightly above normal. After 6 months PCR analysis of viral RNA not detected, the level of Alt was normal. With repeated liver biopsy established the lower YOKE 2 points.

Before treatment the synthesis of IFN-γ: prior to the introduction of interferon-α and 10.5 PG/2×106CL, after 4.5 hours after the first injection of interferon-α - 25 PG/2×106CL Synthesis of IL-4: prior to the first injection of interferon-α and 26.9 PG/2×106class. after introduction of 26.3 PG/2×106cells. The ratio of rates of synthesis of IFN-γ/IL-4 prior to the introduction of interferon-α - 0,39, after the first injection - 0,95.

The given clinical example demonstrates that the patient L-BA formation after 24-week interferonoterapii virological response was defined more than two-fold increase in synthesis of IFN-γ and the ratio of the TN-γ /IL-4 after the first injection of interferon-α.

Example 2. Patient H to VA, age 39, laborer, case history No. 5464. Was treated in the gastroenterological Department of the regional hospital with 25.10.99 on 6.11.99,

Diagnosis. Chronic viral hepatitis C (HCV RNA +) with the least pronounced activity. Chronic acalculous cholecystitis without exacerbation.

Complaints of recurrent pain in the right hypochondrium, fatigue. The above complaints bother about six months. In 1980 underwent surgery on forearm, no more hurt, alcohol is not abused.

Objectively. The condition is satisfactory. The skin is a normal color. The rhythmic heart sounds, pulse rate 88 in 1 minute, HELL 120/85 mm Hg Above the light vesicular breathing. The abdomen is soft, painless, liver is palpable 1 cm below the edge of the right costal arch, moderate density, painless. Sizes karlovu 13×9×7 see Spleen not palpated.

General blood and urine tests without pathology. Blood bilirubin 15,39 Ámol/l Alat 56 U/l, AST 42 U/l, GTT 27 U/l, alkaline phosphatase 151 IU/L. PETIT 92%. Total protein 72 g/l, albumin 54%, globulins: α - 15%, β - 11%, γ - 20%. Thymol test 7,7%

Viral markers: aHCV +, aHCV IgM +, HCV RNA +. Markers of HBV infection, HIV negative.

Ultrasonography. Liver: right lobe 136 mm, left - 94 mm, echo stand the Shen, the fabric is non-uniform. Intrahepatic ducts are not expanded. Portal vein 11 mm, splenic - 6 mm Choledoch 5 mm Gall bladder 56×27 mm, strain the two curves, the walls are sealed. Pancreas: head 28 mm, the body of 16 mm, the tail is 18 mm, the tissue is homogeneous. Spleen 107×48 mm, fabric uniform.

Liver biopsy. Fragments of liver tissue with a few small portal tracts, which expanded sclerosis with predominantly fibroblasts. Hepatocytes in the hydropic state and globular fatty dystrophy.

Conclusion. Chronic hepatitis, active low due to the lobular component. Index Knodell 3 points. Index Desmet 1 point.

The synthesis of IFN-γ: prior to the first injection of interferon-α and-8.5 PG/2×106class. after the first injection to 10.5 PG/2×106CL Synthesis of IL-4: before and after the first injection of interferon to the patient - 25,0 PG/2×106class. and 26.5 PG/2×106class. respectively. The ratio of IFN-γ/IL-4 prior to the first injection of interferon 0,34, after 4.5 hours after administration 0.39 per.

The patient was started on treatment with interferon-α (IFN) according to the standard scheme - ME 9 million per week. After 6 months: I feel OK, transaminases within normal limits, but the blood is RNA virus C.

Thus the negative is esponder with chronic hepatitis C were determined negligible (less than 2-fold) increase in spontaneous synthesis of IFN-γ and the ratio of IFN-γ/IL-4 after the first injection of interferon-α.

The use of the proposed method prior to treatment with interferon-α to establish a change of the synthesis of IFN-γ and IL-4 mononuclear cells, characteristic for the formation of early virological response or lack thereof.

The study is safe, invasive intervention is limited to two drawing blood from a vein, is available for practical health care institutions, there are no additional costs for equipment and training, not time-consuming.

Sources of information

1. Hepatitis C: consensus of 2002. National Institute of health (USA), 10-12 June 2002 // Viral hepatitis: achievements and prospects. - 2002. No. 2. - P.3-11.

2. Ivashkin V.T., Mammaev S.N., Breverb S.A. and other Mechanisms of immune evasion" in viral hepatitis // ROS. Journe. Gastroenterol., gepatol., coloproctol. - 2000. No. 5. - P.7-13.

3. Ivashkin V.T., breverb S.A. Clinical Hepatology today and tomorrow // ROS. Journe. Gastroenterol., gepatol., coloproctol. - 2002. No. 1. - P.4-9.

4. Stroganov GI, Nikitin I.G. Chronic viral liver disease is a systemic infection? // Ter. arch. - 1998. No. 2. - P80-82.

5. Kanai K., M. Kako, H. Okamoto HCV genotypes in chronic hepatitis With and response to interferon // Lancet. - 1992. - Vol.339. - P.1543.

6. Pagliaro L., Craxi A., Cammaa C. et al. Interferon alpha for chronic hepatitis : An analysis of pretreatment clinical predictors of response // Hepatology. - 1994. - Vol.19. - P.820-828.

7. Tsai, S., Liaw Y., Chen M. et al. Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity // Hepatology. - 1997. - Vol.25, No. 2. - P.449-458.

8. Beloborodov AI, Crnogorac GA, Savchenko IV and other Possibilities for prediction of adverse outcomes interferonoterapii in chronic viral hepatitis // ROS. Journe. Gastroenterol., gepatol., coloproctol. - 2004. No. 1. Mgr. No. 22. - P.6(9).

9. Serov N.A., Postnikova so-CALLED. Prediction of positive response to standard therapy of chronic hepatitis C // ROS. Journe. Gastroenterol., gepatol., coloproctol. - 2004. No. 1. Mgr. No. 22. - P.23 (80).

10. Sharara, A.I., C.M. Hunt, J.D. Hamilton Hepatitis C // Ann. Intern. Med. - 1996. - Vol.125. - P.658-668.

11. Ferrante, A., Thoung I.H. A rapid one-step procedure for purification of mononuclear and polymorphonuclear leukocytes from human blood using a modification of hyppaque-ficoll technique // J of lmmunological method. - 1978. - Vol. 24. No.1/2. - P.389-394.

12. V.J. Desmet, M. Gerber, Hoofhagle J.H. et al. Classification of chronic hepatitis: Diagnosis, grading and staging // Hepatology. - 1994. - Vol. 19. - P.1513-1520.

A method for predicting treatment outcomes of patients with chronic viral hepatitis With interferon-αinvolving the use of interferon-αand, wherein the determined synthesis in vitro IFN-γ and IL-4 by peripheral blood mononuclear cells before and after 4.5 h after the first dose of interferon-αand identify more than a twofold increase in the synthesis of IFN-γ and the relationship of the synthesis of IFN-γ /IL-4 predict the development of virologic response during the 24-week interferonoterapii, and in identifying less than twice the growth of the synthesis of IFN-γ and the ratio of synthesis of IFN-γ/IL-4 predict the absence of a virologic response.



 

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