Cycloferon efficacy of therapy of chronic hepatitis B (results of randomized multicentre study)

The best therapeutic effect in the treatment of patients with chronic hepatitis B was observed with the use of cycloferon in the scheme of the antiviral therapy. The combination of cycloferon with lamivudine provided complete stable remission in 54.1% of the patients, whereas the use of a-interferon in combination with cycloferon provided remission in 44.1% of the lamivudine-resistant patients. The use of cycloferon in the therapy of chronic hepatitis B made it possible to lower the frequency and manifestation level of the side effects and prevented the lamivudine resistance development and generation of the virus mutants.     

Cycloferon efficacy in viral and bacterial diseases of children (clinical review)

The authors' findings and literature data on the pharmacotherapeut efficacy of cycloferon, an interferon inductor (immunomodulators) are described. The drug effect in the treatment of various socially significant children' diseases, including acute respiratory tract viral infection, bronchial asthma, allergic conditions with infection protection disturbances, mycoplasmic infection, bronchopulmonary complications of acute respiratory tract viral infection with low intensity of free radical oxidation is indicated. The use of cycloferon at the background of vaccination was shown to provide inhibition of the autoimmune processes causing postvaccinal complications in frequently ill children. The results of the use of cycloferon in the treatment of gastrointestinal tract and intestinal infections of both the viral and bacterial genesis are discussed. Cycferon is recommended to be used for correction of the intestine dysbiosis (the microflora level came to normal in 95% of the children). The use of the drug in surgical pathology and in particular in appendicular peritonitis for decreasing the postoperative complications and correction of the immune disturbances due to chronic viral hepatitis C and B in children under the complex therapy is described. The cycloferon safety and efficacy were confirmed by the postmarketing randomized trials.     

Clinical efficacy of cycloferon in complex therapy of infectious mononucleosis in pediatrics

The results of the cycloferon use in therapy of 80 children at the age of 1 to 15 years with infectious mononucleosis are presented. The children were divided by chance sampling into two comparable groups of 40 subjects each. In the first group the children in addition to the standard therapy were treated with cycloferon for 10 days, intramuscularly or orally depending on the age. The reference group included the patients under the standard therapy alone. The efficacy of the drug was evaluated by reduction and more rapid disappearance of the main clinical symptoms of the disease. The improvement of certain laboratory indices, including those of the liver protein synthesis function were recorded, that allowed to reduce the hospitalization term. No side effects of the cycloferon use were observed.     

Evaluation of safety and pharmacotherapeutic efficacy of cycloferon in treatment of Astrakhan rickettsial fever

Clinicopathogenetic impact of cycloferon, an endogenous interferon inductor, on the process of Astrakhan rikettsial fever, its complications and outcomes was analysed. The treatment scheme with addition of cycloferon to the complex therapy was optimized. The specificity of the disease clinical process and the level of the interferon status in the patients treated with cycloferon alone or with combination of the standard therapy and cycloferon was shown. It was observed that in the patients with moderate severity of the disease the combined use of the standard therapy and cycloferon was in favour of arresting the disease clinical signs (fever, headache, weakness, eruption, hepatomegaly, arthralgia and myalgia, lymphatic gland inflammation, primary affect) and lowered the hospitalization term vs. the standard therapy alone. In the patients with moderate severity of the disease the levels of the serous interferon-alpha before the treatment were found lower, while those of interferon-gamma were higher. The use of cycloferon in the treatment scheme resulted in increase of the interferon-alpha levels and decrease of the higher levels of interferon-gamma. The standard therapy in combination with cycloferon in the patients with moderate severity of the disease provided changes in the immune status: increase of the relative content of T- and B-lymphocytes and normalization of their absolute number. Normalization of the phagocytic activity and the coefficient of the active phagocytes, as well as increase of the phagocytic index, the levels of immunoglobulins G, A and M and the number of the circulating immune cells were stated. The standard therapy with addition of cycloferon resulted in normalization of the levels not only of succinic denydrogenase, lactate dehydrogenase and glucose-6-dehydrogenase but also of alpha-naphthylacetate esterase and alpha-naphthylbutirate esterase in the neutrophils, as well as of the whole spectrum of the monocyte enzymes, except NAD-diaphorase. The adverse reactions were observed in 2.5% of the cases (9 subjects). All of them were mild and did not require discontinuation of the drugs use.     

Clinicoimmunological monitoring of therapy in patients with associated forms of yersiniosis

Characteristics of the clinical process and immunological profile in children with yersiniosis as a monoinfection or in association with acute intenstinal infections and virus hepatitis A are presented. The efficacy of the immunotropic therapy with cycloferon, an interferon inductor, and recombinant interferon in the patients with the viral and bacterial association of the disease (yersiniosis + hepatitis A) and initial disbalance of the serum cytokines was estimated. Dependence of the interferon clinicolaboratory efficacy on the initial levels of serum y-interferon, IL2 and IIA, promoting shorter terms of hyperthermia, diarrhea syndrome and cytolysis syndrome was shown. It allowed to optimize the scheme of the pathogenetic therapy of Yersinia mixed infection.     

Improvement of herpetic stomatitis therapy in patients with chronic tonsillitis

To determine the clinicopathogenetic efficacy of cycloferon liniment in combined therapy of herpetic stomatitis, 60 patients with herpetic stomatitis and chronic tonsillitis were examined and treated. It was shown that the use of cycloferon liniment in the combined therapy of herpetic stomatitis in the patients with chronic tonsillitis allowed to lower the infection load in the parodontal recesses and the local inflammation, to normalize the immunity indices and to reduce the level of the endogenous intoxication, that provided acceleration of the recuperation processes and decreased the frequency of stomatitis backsets.     

恩替卡韦联合血浆置换治疗慢性乙型重型肝炎的研究

目的初步探讨恩替卡韦联合血浆置换治疗慢性乙型重型肝炎患者的疗效。方法选取40例慢性乙型重型肝炎患者,在常规内科治疗及恩替卡韦0.5 mg/d抗病毒治疗基础上联合血浆置换治疗。同时选取38例慢重肝患者为对照组,给予常规内科治疗及恩替卡韦0.5 mg/d抗病毒治疗。比较2组患者在慢性乙型重型肝炎早、中和晚期存活率的差异。结果联合血浆置换组生存率为72.5%,而对照组生存率为50%(χ2=4.168,P=0.041)。其中,中期慢重肝患者联合血浆置换治疗,其生存率为72.2%,而对照组生存率为38.9%(χ2=4.050,P=0.044),早期和晚期慢重肝患者联合血浆置换治疗,其生存率与对照组比差异无统计学意义(P0.05)。结论慢性乙型重型肝炎中期患者采用恩替卡韦联合血浆置换治疗能提高患者生存率。     

Antimycotic therapy of experimental infections caused by dematiaceous fungi

Experimental infections of mice with Wangiella dermatitidis and Fonsecaea pedrosoi provided a model for evaluating new antifungal agents or new combination therapy. In our models flucytosine exerted a dose-related therapeutic effect on the acute and on the more chronic infection. In the acute Wangiella infection amphotericin B also showed therapeutic activity whereas in the Fonsecaea model the effect was weak. The azole derivative ICI 153066 was the most efficacious drug in the Wangiella model whereas ketoconazole was inactive. The effect on colony-forming units of fungi in the brain was stronger with all drugs tested than the effect on survival time. Combination therapy with flucytosine + amphotericin B showed reproducible potentiating effects whereas the combination of flucytosine + ketoconazole was only additive and amphotericin B + ketoconazole showed no synergistic effect.     

Interrelation between the activity of hepatitis, liver fibrosis and immune status in children with chronic hepatitis B and C

The lesion of the liver in viral hepatitis was found to depend on the state of the immune system. Relationship between the content of lymphocyte subpopulations (CD3+, CD4+, CD8+, CD20+) in the blood and immunoglobulins (IgG, IgM, IgA) with parameters of semi-quantitative evaluation of the activity of hepatitis and the stage of liver fibrosis in children with chronic virus hepatitis B, C, B + C was studied. The characteristic feature of all hepatitis was a decrease in the number of T lymphocytes CD4+ below the normal level and an increase in the content of B lymphocytes. The correlation between the morphological activity of hepatitis and the amount of T lymphocytes CD8+ was established only in chronic hepatitis B. In chronic hepatitis B and B + C the absolute amount of blood lymphocytes decreased with the increase of the age of the patients, but in chronic hepatitis B this was accompanied by the decrease of the morphological activity of hepatitis and in hepatitis B + C by its increase. The amount of lymphocytes CD4+ rose with the increase of liver fibrosis in chronic hepatitis B. In children with chronic hepatitis C and B + C the amount of blood lymphocytes was found to be unrelated to the morphological activity of hepatitis.     

Cellular immune responses to the hepatitis B virus polymerase

CD4 T cells play an important role in hepatitis B virus (HBV) infection by secretion of Th1 cytokines that down-regulate HBV replication, and by promoting CD8 T cell and B cell responses. We have identified and characterized 10 CD4 T cell epitopes within polymerase and used them to analyze the immunological effects of long-term antiviral therapy as compared with spontaneous recovery from HBV infection. Candidate epitopes were tested for binding to 14 HLA-DR molecules and in IFN-gamma ELISPOT and cytotoxicity assays using peripheral blood lymphocytes from 66 HBV-infected patients and 16 uninfected controls. All 10 epitopes bound with high affinity to the most prevalent HLA-DR Ags, were conserved among HBV genomes, and induced IFN-gamma responses from HBV-specific CD4+ T cells. Several epitopes contained nested MHC class I motifs and stimulated HBV-specific IFN-gamma production and cytotoxicity of CD8+ T cells. HBV polymerase-specific responses were more frequent during acute, self-limited hepatitis and after recovery (12 of 18; 67%) than during chronic hepatitis (16 of 48 (33%); p=0.02). Antiviral therapy of chronic patients restored HBV polymerase and core-specific T cell responses during the first year of treatment, but thereafter, responses decreased and, after 3 years, were no more frequent than in untreated patients. Decreased T cell responsiveness during prolonged therapy was associated with increased prevalence of lamivudine-resistant HBV mutants and increased HBV titers. The data provide a rationale for the combination of antiviral and immunostimulatory therapy. These newly described HBV polymerase epitopes could be a valuable component of a therapeutic vaccine for a large and ethnically diverse patient population.     

Dynamics of immunological indices in patients with chronic viral hepatitis B and the effect of thymalin therapy

The work deals with the results of the study of T-lymphocytes and their subpopulations (active, thermostable, theophylline-sensitive and theophylline-resistant) in 102 children with chronic viral hepatitis B, depending on the effectiveness of thymalin therapy. The sensitization of lymphocytes to specific antigens was studied. Among patients with chronic viral hepatitis B and cirrhosis of the liver the homozygous phenotype of haptoglobin is registered essentially more frequently (63.6% and 82.4% respectively) than among healthy persons (44.0%). The patients of this group showed a decrease in the number of T-lymphocytes, disturbances in the suppressor/helper ratio: hypersuppression in persisting hepatitis and hyposuppression in active hepatitis. In 71.6% of cases thymalin therapy produced an effect manifested by clinico-biochemical remission, an increase in the number of T-lymphocytes, thermostable cells and the normalization of the T-suppressor/T-helper ratio. In these patients sensitization to HBsAg essentially decreased (from 30.5% to 13.9%), while sensitization to human liver lipoprotein retained its high level even after treatment with thymalin.     

Therapeutic efficacy of various formulations of cycloferon in the treatment of infectious mononucleosis in children

One hundred twenty six children at the age of 4 to 7 years with infectious mononucleosis were observed. The subjects under the complex therapy were treated with cycloferon suppositoria (1st group), intramuscular cycloferon (2nd group) or placebo (3rd group). The results demonstrated similar therapeutic efficacy of the parenteral cycloferon and rectal suppositoria (a novel cycloferon formulation).     

Interferon-Alpha-2a and Zinc Combination Therapy in Children with Chronic Hepatitis B Infection

Zinc has been reported to enhance the response to interferon (IFN) or PEG-IFN plus ribavirin therapy, improve liver function, and ameliorate hematologic side effects in patients with chronic hepatitis C. However, the role of zinc supplementation during IFN therapy in chronic hepatitis B infection (CHB) remains unclear. We therefore aimed to report the results of zinc and IFN-alpha-2a therapy in children with CHB. Twenty-two naive, HBeAg-positive children (mean age 10.4 ± 4.4 years) received IFN-α2a (9 MU/m² sc) for 6 months plus peroral zinc (7.5 mg/day for <10 years and 10 mg/day for >10 years) for 12 months. Serum zinc, alanine aminotransferase (ALT), complete blood count, hepatitis B virus DNA (HBV DNA), and serological markers were measured. Histological (HR) and sustained response (SR) were evaluated at 6 months after completion of therapy. Normalization of ALT, HBeAg seroconversion, and HBV DNA < 10,000 copies/ml were considered as SR. HR was defined as decrease in Knodell histological activity index (HAI) score by at least 2 points compared to baseline. End of therapy ALT level and log HBV DNA were significantly lower than pretherapy levels (p = 0.001 and p = 0.001, respectively), while zinc level was not different. Portal inflammation score significantly decreased after therapy (p = 0.043), however, total HAI and other HAI components were not different. SR and HR were 25% and 52.9%. In conclusion as a first study investigating the effect of zinc and IFN combination therapy in children with CHB, SR and HR rates were not better than previously reported monotherapy or combination therapies.     

拉米夫定联合左旋咪唑涂布剂治疗E抗原阳性儿童慢性乙型肝炎

目的分析拉米夫定联合左旋咪唑涂布剂治疗21例HBeAg阳性儿童慢性乙型肝炎的近、远期疗效。方法采用统一检测方法和评价标准,分析拉米夫定联合左旋咪唑涂布剂治疗HBeAg阳性的儿童慢性乙型肝炎（儿童组）的近期疗效,HBVYMDD发生率及停药后的远期疗效,并与同期治疗的HBeAg阳性成人A组（拉米夫定＋左旋咪唑涂布剂）与成人B组（单用拉米夫定）的相关指标比较,进行,检测和P检验。结果儿童组与成人A组及成人B组治疗结束时血清学、病毒学、生化学单项应答率分别为52．4％、34％、28．5％;90．5％、74．9％、62．8％;85．7％、82．9％、75．9％;完全应答率分别为52．4％、32％、25．5％;HBVYMDD变异率分别为14．3％、18％、32．12％;停药后1年持久应答率分别为90．9％、75％、51．43％。结论对ALT≥正常上限2倍的慢性儿童乙型肝炎,拉米夫定联合左旋咪唑涂布剂近远期疗效均明显优于单用拉米夫定者,应扩大临床验证,谨慎而果断应用。     

Minimization of endogenous intoxication syndrome by individual choice of drugs for therapy of chronic hepatitis

The results of clinical and laboratory examination of 107 children suffering from chronic hepatitis B or C were analysed. The biochemical criteria of the endogenous intoxication were investigated. Specific blood tests with antiviral drugs were conducted before the treatment and individual therapy schemes were assigned according to the tests' results. The early and sustained virological response rates during the individual antiviral treatment of the children with chronic hepatitis C proved to be 70.83 and 62.5% respectively.     

New therapeutic vaccination strategies for the treatment of chronic hepatitis B

Chronic hepatitis B virus (CHB) is currently treated with either interferon-based or nucleot(s)ide-based antiviral therapies. However, treatment with pegylated interferon alpha results in a durable antiviral response in only about 30% patients and is associated with side effects. Most patients receiving nucleot(s)ide analogue treatment do not establish long-term, durable control of infection and have rebounding viremia after cessation of therapy. Thus, novel therapy strategies are necessary to achieve the induction of potent and durable antiviral immune responses of the patients which can maintain long-term control of viral replication. Therapeutic vaccination of HBV carriers is a promising strategy for the control of hepatitis B. Here the authors review new therapeutic vaccination strategies to treat chronic hepatitis B which may be introduced for patient treatment in the future.     

慢性病毒性肝炎研究进展

近年,慢性病毒性肝炎研究领域有较大进展,慢性乙型肝炎病毒（HBV）感染,虽然有了应用广泛、历史较久、且效果较好的疫苗,但迄今仍是世界范围肝硬化和肝癌的主要诱因。传染途径可经产道、性接触和非肠道途径（包括静脉吸毒、血制品等）。成年病人有少有变慢性,但一岁以下患儿90％变成慢性肝炎。慢性肝损伤的临床表现可以是轻微的炎症重到晚期肝硬化,程度不等。α干扰素（IFNα）是治疗活动性肝炎的产宰药物,单核苷酸类药物（lamivudine和adefovir）也具有同样的疗效。晚期肝病和肝癌患者可进行移植,但异常伴发移植物的感染。乙型肝炎免疫球蛋白和新型抗病毒药物联合应用,可降低移植物感染的严重性。丙型肝炎病毒（HCV）在20世纪后期感染了大约1％的世界人口。这中RNA病毒非经口传播,绝大多数病人变成慢性肝炎,约20％逐渐演变成肝硬化或肝癌。用IFNα和病毒唑（Ribavirin）联合治疗,约40％病人的病理表现有所改善。肝移植对某些病例是适宜的,但移植物感染仍是悬而未决的问题,新发现的庚型肝炎病毒（HGV）和TT病毒目前认为并不引起严重的肝损害。     

Serum zinc as a factor predicting response to interferon-alpha2b therapy in children with chronic hepatitis B

Although it has been unclear why more than 50% of children with chronic hepatitis B virus infection do not respond to interferon therapy, in some instances resistance to interferon probably is caused by an inability to stimulate appropriately cellular immune responses to hepatitis B virus. It is known that immune integrity is tightly linked to zinc status. We examined the relationship between serum zinc levels and response to interferon (INF)-α therapy in children with chronic hepatitis B. Twenty-five children with chronic hepatitis B infection were injected with 5 × 10⁶ units/m² recombinant IFN-α 2b subcutaneously three times weekly for 9 mo. Children were followed for at least 9 mo after the end of therapy. Sustained response was obtained in eight (32%) patients. Although initial serum zinc and alanine aminotransferase levels were significantly higher; initial hepatitis B Virus (HBV)-DNA values, hepatic activity index, periportal necrosis, and fibrosis scores were significantly lower in sustained responders than in nonresponders. Mean baseline serum zinc, alanine aminotransferase and HBV-DNA values, histologic activity index, periportal necrosis, and fibrosis scores were predictive of response to IFN-α 2b therapy. These findings suggest that serum zinc levels might be used as a factor predicting response to interferon-α 2b therapy, and so may help in identifying those children with a better chance of response.     

Chronic hepatitis B exacerbation following a short prednisone therapy resulting in death]

A case of a 36-year male patient with chronic active hepatitis B is described. A short-term prednisone therapy resulted in the exacerbation of the disease leading to hepatic failure and patient's death. A short-term corticotherapy in some patients with chronic active hepatitis B may prove fatal.