Скворцов В.В.
Статья в Чехию по терапии хронических гепатитов на англ.языке (2006)

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Emelyanov D.N., Sviridenko O.J., Skvortsov В.В., Myazin R.G.

The current tactics of acute and chronic viral hepatitis antiviral treatment.

Volgograd State Medical University

Department of propedeutics of intrinsic diseases

   Viral hepatitis infections represent the most serious medico-biological and social problem of mankind. Worldwide parenteral transmitted viral hepatitis accounts for an estimated 500 million of infected individuals. Most of them will develop chronic viral hepatitis infections with possible serious outcomes such as liver cirrhosis and hepatocellular carcinoma. According to the CART, since 1961 chronic hepatitis and liver cirrhosis moved from 10th to 5th among the top 10 leading causes of death in the USA and Western European countries [1,2]. At the moment eight different types of human viral hepatitis are recognized - A, B, C, D, E, F, G and TT. Recently reported SEN virus, which is transmitted via blood transfusion, was proposed as an etiological factor of neither A nor G type of hepatitis infection [3]. Nowadays specific markers for all types of hepatitis viruses, except F, could be detected by laboratory tests. In the majority of regions of the world and the Russian Federation populations are predominantly infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). HBC and HCV infections are characterized by a continuously increasing case rate and high ratio of complications. Intravenous drug use has also led to wide circulation of HBV and a HCV infections. Between 50 and 90 % of intravenous drug users are infected by these viruses [4,5,6].
   The purpose of our review is to discuss antiviral therapy agents used for the treatment of virus hepatitis infections at present.
   In 1970-1980 there was an intensive search for a treatment of acute and chronic viral hepatitis infections. In many countries viral replication suppressors and drugs designed to eliminate hepatitis viruses were developed and tested. Theoretical and clinical research of the following types of drugs are carried out at the moment: interferons (IFN), antiviral agents (nucleoside analogues), interferon inducers, immunomodulating factors, blockers of a code of viruses (drugs active on molecular level, which could prevent/slow down viral replication or provide full inhibition of viral gene expression). This latest strategic direction of therapy will big prospects in the future [1,7].
      -- Interferons:
   At the moment Interferons (IFNs) are recognized as the most effective agents in the treatment of viral hepatitis infections. IFNs are a group of autogenic glycoproteins which have a simultaneous antiviral effect (an activation/suppression of cellular genes which leads to inhibition of the viral DNA (RNA) synthesis) and an immunomodulating effect (stimulation of antigens HLA expression on cellular membranes and enhancement of cytotoxic activity of T cells and natural killer (NK) cells).
   IFNs could be grouped in two types: IFNs of the first type have mainly an antiviral effect and work as inhibitors of viral replication (22 subtypes of IFN-? and 1 subtype of IFN-?). The second type of IFNs display immunomodulator activity (IFN-?).
   There are 3 immunological types of INFs: IFN-? , IFN-? and IFN-?. Natural INFs could be produced by extraction and purification from stimulated monocytes (limphoblast IFN-?), B cells (leukocyte IFN-?), tissue culture of fibroblasts (IFN-?) and T-cells (IFN-?). Artificial IFN-? are produced as highly pure recombinant unique subtype of IFN-?.
   There are a number of recombinant IFN-? variants available, among them IFN-?-2a (Roferon A, produced by Hoffmann la Roche LTD, Switzerland), IFN-?-2b (Intron A, produced by Schering Plough, USA; Reaferon-ES produced by the Vector-Pharm, Russia), IFN-?-2c and lymphoblast IFN-? (Vellferon produced by, Glaxo Wellcome, UK). In the recent years pegylated recombinant INFs of prolonged action became available in a clinical practice (PEGASYS, produced by Hoffmann la Roche LTD, Switzerland and Pegintron produced by Schering Plough, USA). PEGASYS is a pegylated form of IFN-?-2a, which utilizes a 40 kDa branched polyethylene glycol (PEG) molecule. Pegintron a pegylated form of IFN-?-2b, which utilizes a 12 kDa PEG molecule. Pegylated INF have the greatest antiviral activity among IFN-? drugs [7].
   Nowadays recombinant IFN-? are the drugs of choice for treatment of hemocontact hepatitis infections. Active viral replication is a main clinical evaluation for the antiviral treatment. Thee level of replication is assessed by the Enzyme immunoassay (EIA) for viral hepatitis antibodies: HBe-Ag (HBV), anti-HDV-IgM (HDV) or detection of viral DNA (HBV) or RNA (HDV and HCV) with PCR assay.
   Congenial prognostic factors for the patients with chronic HBV, HCV, HDV infections are short duration of disease (less than 5 years), young age (younger than 45 years), absence of histological attributes of a liver cirrhosis , a low aminotransferases level in the blood serum (no more than 3 fold of normal level), low concentration of iron in liver tissue (less than 650 ?g/g of native mass) and normal index of blood serum iron (17-22?M) [1,7,8,9,10].
   Nonprolonged IFN-? treatment is noncompatible with decompensated liver cirrhosis, serious concomitant cardiovascular diseases, mental diseases, use of narcotics, alcoholism, autoimmune diseases and chronic renal failure.
   Regime of average doses - 5 МU 3 times a week for 2-3 months, then 3 МU 3 times a week for 4-12 months.
   Regime of small doses - 3 000 000 МU 3 times a week for 3 months.
   The regime of high doses is often applied at an acute phase of viral hepatitis infections. Chronic viral hepatitis infections treatment begins with a regime of high or average doses, in cases of unsatisfactory tolerance to a IFN regime of small doses is recommended [8,9].
   The assessment of INF therapy efficacy in case of treatment of chronic viral hepatitis infections is judged by returning of transferase level to normal, negative EIA and PCR and morphological changes of a liver tissue after course of treatment [6,7,11,12].
   The most common adverse effect of INF therapy is flu-like syndrome (fever, myalgia, headaches), which could occur in the first or second week of treatment, clinical observations show that symptoms can be reduced if INF is injected in the evening. Other adverse effects include diarrhea, sleep disturbances, lost of weight, fatigue, leukopenia, thrombocytopenia (less 70x10 \L) and also development of a thyrotoxicosis (12 % of patients )[13]. The majority of adverse effects are more likely to occur with higher doses of medication and can be removed by carefully selecting the dose of IFN [1,8,9].
   Efficacy of mono-therapy by unpegylated INF is low. Only a third of patients with a chronic HBV and HCV infection and 10 % of patients with an HDV infection positively responded (absence of viral replication , normal transpherase level in 6 months after end of mono-therapy by unpegylated INF) to the IFN treatment used in usual doses. In view of this, the majority of authors now agree that treatment of hemocontact viral hepatitis infections can not be, and should not be, carried out only with INF therapy [7, 9, 12, 14, 15]. The necessity of simultaneous use of several medicines, capable of influencing various stages of viral replications and immune system as a whole became obvious. However IFNs continue to remain a basic component of treatment. For example, in cases of relapse after the first course of monotherapy IFN-?, combinations of IFN-? with lamivudin for HBV infection [9] or IFN-? with ribavirin for HBC infection were used with a positive effect for a greater part of patients [12].
   Now, after the start of application in clinical practice of the recombinant IFN-? with prolonged effect (pegylated), new opportunities of the more effective treatment of viral hepatitis infections have been discovered. Affiliation of INF with PEG leads to the augmentation of an effective half-life of the drug due to the reduced rate of a clearance. Antiviral activity of the pegylated IFN-? increases as a result of prolonged life and lower fluctuations of IFN-? concentration in blood. Essentially, the important advantage of the pegylated IFN-? compared to short life recombinant IFN-? is the possibility of their use in patients with liver cirrhosises, because pegylated IFN-? can be degraded even without intact hepatic hemoperfusion [16]. Besides, IFN-? with prolonged effect are less antigenic and can be used in patients with cardiologic diseases, disturbances of kidney functions and hemoglobinopathies [17]. In comparison with others IFN-? , the dose of a pegylated IFN-? is calculated individually depending on weight of each patient. Also the use of pegylated IFN-? is more convenient (one weekly injection). Pegylated IFN-? is administrated subcutaneously in a dose of 1.5 Ѕkg/kg body mass, weekly for 6-12 months.
   Recent publications, relating to investigations of the clinical efficacy of recombinant IFN-? with prolonged effect in combination with rebetol (ribavirin), have shown that such combinational therapy has the highest antiviral activity in cases of HCV infection. Results obtained with PEGASYS are even more encouraging [7].
      -- Nucleosides analogues :
   Nucleosides analogues are a group of agents, which interfere with hepatitis viruses genomes.
   Lamivudine (Zeffix, Epivir 3TC produced by Glaxo Wellcome, UK) inhibits RNA-depended reverse transcriptase, which is needed for the transcription of HBV genome from RNA to DNA. Lamivudine has high antiviral activity towards HBV. It reduces the level of mitochondrial DNA and could induce insignificant mitochondrial toxicity [1, 18]. Treatment with lamivudine is recommended for patients with the proved replication of HBV (presence НВе-Аg and DNA HBV), 3x and more increase from the normal level of alanine transferase, abnormal liver histology and also for patients on a stage of a decompensation of chronic hepatitis and liver cirrhosis with replicational HBV [9,18].
   For children younger than 12 years old, lamivudine is prescribed daily in a dosage of 3 mg/kg body mass, for children older than 12 years as a daily dose of 100 mg and for adults as a daily dose of 100-300 mg for 12 weeks.
   The criteria for the efficacy of lamivudine therapy are the reduction of HBV DNA concentration, the disappearance HBe-Ag and the appearance of anti-HBV antibodies, the returning of alanine transferase level to normal, a decrease in the advance of liver fibrosis and the slowing down of transition to a liver cirrhosis [18].
   Lamivudine monotherapy is well tolerated by patients. Adverse effects (fatigue, headache, nausea, fever, leucopenia and a depressive syndrome) were observed only for 1-5 % of patients [18].
   Lamivudine therapy allows the suppression of HBV replication and reduction of HBV DNA level up to the minimal values after 1-3 months of treatment [19]. Prolonged lamivudine therapy (1 year and longer) leads to a reduction of HBV DNA level, stable normalization of the alanine transferase level and improvement of the liver histology (according to a puncture biopsy) for 65 % of patients [20]. For the other 35 % of patients the HBV DNA level in blood serum increases again but does not return to the starting level even after one or three-year course of therapy. Besides, in cases of long term lamivudine therapy, the lamivudine resistant type of HBV with mutations in the YMDD region could appear in patients [19]. The probability of appearance of such mutation is 24 % (after one year of therapy) or 49 % (after 3 years of therapy)[18]. In pilot studies patients with HBV infection in presence of a mutated in YMDD region HBV could be treated with adefovir, which is capable of inhibiting a reverse transcriptase of mutated HBV. But adefovir treatment can not be used without combination with lamivudine; otherwise it could lead to the selection of wild type HBV. Also combinations of lamivudine treatment with clevudine, entecavir and empicitabin were tested on patients with HBV infection in presence of a mutated HBV. All these drugs are nucleoside analogues and subject to the different stages of clinical trials [21].
   According to the latest research, lamivudine monotherapy is effective for patients with the HBe-Ag-negative variant of a chronic HBV infection. Tactics for the treatment of HBe-Ag-positive variant of a HBV infection demands a combination of IFN-? with lamivudine for the purpose of increasing efficacy of a specific therapy [22].
   Farmcyclovir (Famvir, produced by SmithKline Beecham Pharmateuticals, Belgium), being an analogue of nucleosides, possesses a similar mechanism of action to lamivudine, but with a lower efficacy. Farmcyclovir suppresses DNA HBV replication and reduces concentration of DNA НВV in blood serum to the minimal identifiable level. Farmcyclovir is prescribed in a dose of 500 mg, 3 times a day for 1-6 months. After a course of ribavirin monotherapy only for 19 % of patients concentration of HBV DNA does not increase again up to the original values [9].
   Ribavirin (Ribavirin, produced by Hoffmann la Roche LTD, Switzerland; Rebetol, prodused by Schering Plough, USA; Vero-ribavirin, prodused by Verofarm, Russia) is a guanosine analogue, which inhibitis viral RNA polymerase and indirectly inhibitis protein synthesis. It has virostatic effect towards many DNA and RNA viruses. The dose of ribavirin is calculated depending on the weight of each patient and on average is 800-1000-1200 mg/day. The drug is prescribed orally twice a day for 12-24-48 weeks. Ribavirin is quite toxic and the most common adverse effects are giddiness, nausea, depression and erythrocytes haemolysis. Besides, even a long term ribavirin monotherapy does not lead to viral elimination. Therefore ribavirin is used in combination with IFN, which could significantly enhance the antiviral effect of the therapy, especially for the treatment of unresponsive to the IFN monotherapy patients and for patients with the unstable effects of IFN therapy [14, 15, 23]. For many years the algorithm of combined intron A and rebetol therapy was officially licensed as antiviral therapy for the treatment of chronic hepatitis infections [7.] Intron A was prescribed 3 times a week IM or SC for 24 weeks and rebetol was prescribed orally in a dose of 800-1000-1200 mg/day twice a day for 24 weeks. The course of such treatment leads to stable reduction/elimination of HCV RNA, reduction in alanine transferase level and reduction of inflammatory-necrosis (according to a puncture biopsy) for 40 % of patients [1]. The new "golden standard" in the treatment of chronic HCV infection is a combinational therapy of pegylated IFN-? (1.5 Ѕkg/kg, SC once a week) with rebetol (> 10,6 mg/kg, 800-1200 mg orally daily) for 6-12 months [17]. In the group of patients treated with combinational pegylated IFN-? and rebetol therapy stable virological response was observed in 72% of cases, in the group with HCV genotype 2 or 3 infection virological response was observed in 94 %, and in the group with HCV genotype 1b infection (most common in Russia) virological response was observed in 63 % [16]. It is necessary to note that the same algorithm of combinational therapy which uses PEGASYS with ribavirin is not yet recommended by the Ministry of Health of the Russian Federation [23]. In recent research of complex antiviral therapy of an HCV infection with russian nucleoside analogue vero-ribavirin the virological effects were comparable with foreign nucleoside analogues at significantly lower cost. Some authors recommend the introduction of vero-ribavirin in to combinational therapy of chronic HCV infection [23].
   Algorithm of treatment for patients with combined HBV and HCV infections has been developed, it includes treatment with recombinant IFN (usually pegylated IFN-?) for the year combined with nucleoside analogues therapy (lamivudine treatment for the first 6 months followed by ribavirin treatment for the next 6 months). In the case of unstable effect such therapy could be prolonged for an additional 24-48 weeks.
      -- Interferon inducers:
   Interferon inducers are drugs combining etiotropic effect directed at virus-activator with immune defence correction. These agents promote the production and release of endogenous interferon. The group comprises both natural and synthetic chemicals of different structure. They induce synthesis of all three immunologic classes of interferons (IFN-?, -? and -?) in different proportions. When used in therapy, interferon inducers are well combined with each other, recombinant IFN-?, immunomodulating factors and chemotherapeutic agents. The application of interferon inducers combined with other preparations often leads to potentiation of their effect [24].
   Interferon inducers belong to the new generation of drugs and have some advantages over recombinant IFN- ?:
   Inducers of interferons have no antigenicity;
   Recombinant IFNs participate in immune response and stimulate nonspecific cytotoxicity of immunocytes. They elicit HLA expression in those cell populations which usually do not express these antigens. It can cause autoimmune response aggravation.
   Some interferon inducers such as amixin are able to start interferon synthesis in selected cells only that has the advantage over polyclonal immunocyte stimulation by recombinant IFN;
   Widely used recombinant IFN based medicines are made with ?--interferon only and this limits their antiviral properties because the presence of all three classes of interferons is vital for effective antiviral protection (this can be achieved by interferon inducers).
   Interferon inducers have their own immunomodulating properties.
   There are over ten interferon inducers currently being used in therapy. They have synthetic as well as natural origin. Some of them are used for prophylaxis and treatment both acute and chronic viral hepatitis [24].
   The table:
   Interferon inducers applied in viral hepatitis treatment
   Chemical nature
   Medicine
   A: Synthetic substances
   Low-molecular weight (aromatic) carbohydrates:
      -- Fluorenones
      -- Acridanones
   Amixin
   Cyclopheron, neovir
   Polymers (double-stranded RNAs):
      -- poly(A) poly(U)
      -- poly(G) poly(C)
   Poludanum
   Polyguacyl
   B: Natural substances
   Low-molecular polyphenols (gossypol derivatives):
   Kagocel
   Ragosin
  
   Amixin (Lancepharm, Russia) is the first of its class peroral inducer of endogenous interferons ?, ?, γ. It combines all the advantages of interferon inducers at the full extent. Being a polyclonal stimulator, amixin induces synthesis of type 1 and 2 interferons in T lymphocytes, intestinal enterocytes of an intestine and hepatocytes. It penetrates blood-brain barrier and induces interferon production in brain cells. The medicine is rather toxic however it does not have mutagen, teratogenic, cancerogenic effects and has no antigenicity. The important feature of amixin is the extended circulation of interferons with therapeutic concentration of 50-100 u/ml in blood serum [25].
   Amixin combines etiotropic, immunomodulating and pathogenetic properties, and it is compatible with antibiotics and other agents of antiviral and antibacterial treatment. This allows using amixin during the treatment of acute and chronic viral hepatitis, flu, various respiratory diseases, herpes, multiple sclerosis, tick-borne encephalitis, AIDS and others.
   Amixin is packaged as 0.125g tablets (6 or 10 per box).
   Amixin treatment of the acute form of type B viral hepatitis involves one course under the following scheme: 2 tablets (0.125g each) are taken on the first day and then tablets (0.125 g each) are administered after every next 48 hours until the total amount reaches 16 tablets. The treatment of the acute form of type C viral hepatitis is as follows: 2 tablets are taken on the first on 0,125 in the first day - г, then in each 48 hours on 0,125 г (20 tablets on a course).
   Amixin treatment of chronic viral hepatitis (B, C or B+C type) is going according to the following scheme: 2 tablets (0.125g each) are taken on the first day and then tablets (0.125 g each) are administered after every next 48 hours until the amount of tablets reaches 20. After that one tablet should be taken every week until the total amount of tablets taken reaches 30 for type B hepatitis or 40 for types C or B+C.
   Neovir (Pharmsynthez, Russia) is a low-molecular-weight synthetic IFN inducer. It is a carboxymethylacrydon derivative with molecular mass less than 300. Neovir activates bone marrow stem cells and eliminates the imbalance in activated T-lymphocyte subpopulations and macrophages. Neovir enhances the activity of natural killers, stimulates interleukin-2 (IL-2) production and normalizes tumor necrosis factor production providing antitumour effect. It also has stimulating effect on the activity of polymorphonuclear leukocytes.
   Neovir is used during the treatment of acute type A and chronic type B and C hepatitis, herpes infection and also for treatment and prophylaxis of the respiratory infections caused by parainfluenza, flu, respiratory syncytial viruses, rhinoviruses, and adenoviruses.
   Neovir is packaged for injections as sterile 12.5 % solution in 2 ml physiologically compatible buffer. The solution is injected intramuscularly. Each ampule for a single injection contains 250 mg of Neovir or the dosage is based on 4-6 mg/kg of weight ratio. The course of treatment consists of 5-7 injections with 48h interval and takes 8-12 days.
   3-4 % of patients treated with Neovir experienced the rise of body temperature up to the subfebrile level and this was accompanied by arthralgias. The therapy should be combined with non-steroidal anti-inflammatory drugs (NSAIDs) [24].
   Cycloferon is methylglucamine salt of carboxymethylacrydon. It is a synthetic analogue of a natural alkaloid from Citrus Grandis. It has prolonged antiviral, anti-inflammatory and immunomodulating action. Cycloferon is capable to induce IFN-?, -? and -? production. The level of interferon induction reaches 60-80 U/ml in blood serum. The endogenous interferon is produced by immunocompetent cells, namely leucocytes, macrophages, fibroblasts and epithelial cells. Cycloferon has low toxicity, no mutagen, teratogenic, embryotoxic or, carcinogenic effect. It shows mild and prolonged immunomodulating action and is compatible with conventional means of therapy.
   The medication is packaged as 12.5 % sterile aqueous solution in 2 ml ampules or lyophilized powder in ampules or vials (0.25 g of active substance). The package contains 5 ampules or vials.
   Cycloferon is effective towards hepatitis viruses of types A, B, C, D, E, vernal encephalitis, herpes, cytomegalovirus, HIV, etc. It is applied for the treatment of a chlamydiosis and in the complex therapy of reactive and rheumatoid arthritis. Cycloferon is injected intravenously or intramuscularly once a day in a dose of 250 mg (2 ml solution) at the 1st, 2nd, 4th, 6th, 8th, 10th and 12th day of treatment. An additional intramuscular injection of 500g (4 ml) of cycloferon is prescribed during the acute stage of disease on the first day. It is possible to repeat the course to ensure the effect of treatment. There are several plans of treatment for each type of hepatitis: type A hepatitis treatment takes 23 days (10 injections), the acute phase of type B hepatitis takes 23 days (10 injections), chronic type B and C hepatitis treatment takes 70 days (3 courses of 10 injections of 500 mg in 4 ml intravenously) [1].
   Poludanum (polyadenur) is a synthetic inducer of interferon consisting of a double-stranded complex of polyadenylic and polyuridylic acids. It acts as an imunomodulator inducing endogenous ?- и ?-interferon production. Poludanum is used for the treatment of type B hepatitis, herpetic keratites and keratoconjunctivites. The treatment of chronic hepatitis involves intravenous injections of 150 mg Poludanum twice a week over 24 weeks. To improve therapeutic effect the patient is transferred to IFN- ? treatment right after the end of the 24 weeks course [24].
   Polyguacyl is a synthetic double-stranded DNA based interferon inducer. It stimulates endogenous interferon production in blood cells and liver followed by some rise of interferon in spleen, lungs, muscle, lymphoid organs. Polyguacyl is effective during the treatment of acute phase of viral hepatitis, acute encephalitises, flu, and rabies. Polyguacyl is applied by intravenous or intramuscular injections as well as hypodermic injections, intranasal and aerosol application.
   Kagocel is a natural interferon inducer based on gossypol derivatives (low-molecular-weight polyphenols).
   It induces the rise in endogenous interferon production in blood, liver, spleen, kidneys, lymphoid tissue. Kagocel is prescribed at hepatitis, tick-borne encephalitis, rabies, flu and viral respiratory diseases. It is admitted via intramuscular injection or orally.
   Ragosin belongs to the same group of natural interferon inducers as Kagocel. It induces endogenous interferon production in blood, liver, spleen and intestine. According to pre-clinical studies ragosin is effective in the treatment of type A and B hepatitis and also neoplasms. The drug is admitted intravenously, intramuscularly, hypodermically and orally [24].
      -- Immunomodulating factors inducing endogenous interferons:
   Cytokines (interleukins)
   Interleukin-2 is a glycoprotein, inducing proliferation and differentiation of T lymphocytes and natural killer cells. IL-2 induces IFN-? producing T-helper functional activity. The increase in IFN-? production owing to IL-2 leads to macrophages activation.
   Interleukin-12 (IL-12) activates ТНJ-lymphocytes and natural killer cells, and also induces IFN-? and IL-2 production.
   IL-2 and IL-12 are prescribed for the treatment of type B chronic viral hepatitis according to the following scheme: 2-5 hypodermic injections of 500 mkg per week over 4-6 months. Nonspecific stimulation by IL-2 and IL-12 inhibits hepatitis B virus DNA replication without destruction of the infected hepatocytes. Biochemical remission is achieved in 20 % of cases. However after the end of the treatment the level of transaminases increases again and only 8 % of patients retain normal parameters [1].
   The human recombinant IL-2 from yeast (Roncoleukin) is a full structural and functional analogue of endogenous IL-2, and it has the same spectrum of functional activity. The treatment of chronic viral type C hepatitis by roncoleukin is going as follows: 500 000 U by intravenous drip 2-3 times per week for 8 weeks. Roncoleukin therapeutic course leads to 40 % of patients having normal biochemical parameters negative PCR [26].
   Glycyrrhizin has some immunomodulating effect namely the increase in T-cells activity, stimulation and production of endogenous IFN-?, increase in phagocytic activity and antibody formation. Glycyrrhizin is used for chronic replicative type B hepatitis treatment. During the first month of the treatment it is admitted by 40 ml 3 times a week, then 2 times a week. Glycyrrhizin therapy continues not less than for 1 year then interferon therapy starts. Such pretreatment improves the subsequent effect of interferon therapy in 60 % of patients with HBeAg seroconversion and some patients observed to have HBV DNA elimination. The direct inhibiting influence of glycyrrhizin on HBV replicative activity is supposed also [1].
   Amantadin is a widely used medication for flu treatment. Recently it was introduced for the treatment of chronic hepatitis. Amantadin therapy involves taking of 1000 mg 2 times a day within 6 months. 30 % of patients had biochemical remission by the end of it and 50 % of them had decreased viremia [10]. There are officially registered plans of chronic hepatitis "triad" therapy in some European countries (Austria, Germany) where amantadin group drugs (Amantadin, Remantadinum, Symmetrelum, Midantanum) are used in 200 mg daily dose alongside with IFN-? and ribavirin. The proven positive response happens in 60-70 % of the patients who do not possess 1b-genotype of virus and in 50% of the patients who do have 1b-genotype of the virus and who did not react on IFN-? monotherapy or had a relapse after it was finished [7].
   Thymusin is a peptide consisting of 28 amino acids that is capable to modify the immune response. It is used in for the treatment of "wild type" (HBeAg +) HBV-infections. 1 mg of thymusin is admitted twice a day during 6-12 months however it is more effective to combine 1mg thymusin twice a day together with 3 000 000 U of lymphoblastoid IFN-3 times a week. After the 1 year course the efficacy of therapy reaches 40-73 % [1].
   All the preparations stated above have already found a place in clinical practice. We could also mention about some promising directions of new antiviral drug development. The use of highly active chemical compounds blocking viral replication enzymes (C-helicase, protease, RNA-dependent RNA-polymerase) could be possible in the nearest future. Also type B chronic hepatitis gene therapy by antisense oligonucleotides and ribozymes is at the clinical test now. Another new method of chronic type C hepatitis treatment is being developed on the base of site-specific targeting and cleavage of viral internal ribosome entry site (IRES) by ribozymes. The result of this approach is "Heptazyme" undergoing the period of clinical tests [12, 17].

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