Rational pharmacotherapy and correction of immunity disorders in children with chronic hepatitis (clinical review)

The data on the efficacy of antivirals and their impact on the virologic and immunologic indices in HCV- and HBV-infected children are presented. The best therapeutic effect in the management of children with chronic virus hepatitis was provided by combined antiviral therapy of different action. In the treatment of babies the drugs of choice could be viferon or cycloferon, for the 2-year older children with chronic hepatitis B the combination of viferon + cycloferon should be recommended and for those with chronic hepatitis C the combination of interal + cycloferon could be used. The cycloferon combination with interferons-a makes it possible to generate the Th1 cellular immune response, to minimize the side effects of interferons and chemotherapeutics and to improve their tolerability. The complex therapy of patients with chronic hepatitis B and lambliasis, using cycloferon and macmiror, provided stable effect, less frequent relapses oflambliasis and minimum side effects of the specific therapy. The repeated isolation of lamblia within a 1-year observation period was recorded only in 16.6% of the children treated with cycloferon vs. the control (40.0%).     

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。     

Immunoglobulin M antibody to hepatitis B core antigen (IgM anti-HBc) as a marker of interferon therapy in patients with persistent hepatitis B virus infection

Immunoglobulin M antibody to hepatitis B core antigen (IgM anti-HBc) was measured by radioimmunoassay in the sera of 96 HBV carriers. IgM anti-HBc was detected in 17 of 66 patients with chronic active hepatitis and in 4 of 11 with liver cirrhosis. This antibody was not present in asymptomatic carriers or in patients with chronic persistent hepatitis. Testing of sequential samples revealed that the presence of IgM anti-HBc indicated active replication of HBV and at the same time an immune response to the virus. The relationship between IgM anti-HBc and the response to interferon (IFN) therapy was also studied. Results showed that IgM anti-HBc is a useful marker of the efficacy of interferon therapy.     

Ribavirin enhances interferon-γ levels in patients with chronic hepatitis C treated with interferon-α

Some patients with chronic hepatitis C respond to interferon (IFN)-alpha treatment, and the efficiency can be improved by combining it with ribavirin. The mechanism of this improvement is unknown. To investigate the effects of these two regimens on the immune responses in 51 patients with chronic hepatitis C, we examined the hepatitis C core antigen-specific proliferative response and cytokine production profiles, natural killer (NK) cell cytotoxicity and cytotoxic T cell function during treatment. The results are as follows: (1) both viral clearance and biochemical normalization occurred more frequently in patients receiving combination therapy; (2) the function of NK cells increased after treatment in the responders of both groups (p < 0.05); (3) the level of IFN-gamma produced by hepatitis C core antigen-stimulated peripheral blood mononuclear cells was higher in patients receiving combination therapy, especially in responders; (4) the core antigen-specific proliferative response decreased after treatment, and (5) in addition, the core-specific cytotoxic T cell activities of five responder patients also increased significantly after therapy. In conclusion, enhancement of immune responses, especially those related to type-1 T helper cell activity, may contribute to better efficacy in combining ribavirin with IFN-alpha for treatment of chronic hepatitis C.     

Therapy for chronic hepatitis C.

BACKGROUND/AIMS: in Hungary, over the past 5 years more than 900 patients with chronic hepatitis C have been examined for treatment with interferon at 16 major hepatology centres, using unified diagnostic and therapeutical criteria. Authors give an account of their experiences on the clinical features of patients with chronic hepatitis C and report the results of the interferon therapy. METHODS: a total of 993 patients--virtually the entire Hungarian hepatitis C patient population who had been referred for interferon treatment--were included in the program. Actually, the sustained efficacy of the therapy was evaluated in 724 cases. Treatment protocols (dose of interferon and duration of therapy) have changed with time from a weekly dose of 3x3 MU IFN for 6 months in the first period, to 3x3-5 MU for 12 months in the second period, and finally in the third period a combination therapy with ribavirin has also been introduced. RESULTS: in the first period, the end-of-treatment response (ETR) was 35%, sustained response (SR) 13%, the second phase schedule resulted in 42% ETR and 22% SR, while in the third period, ETR was 49% and SR 36%, respectively. Fibrosis in histology and baseline pretreatment HCV-RNA level appeared as predictors of response. The duration of treatment and the total dose of interferon exerted a moderate effect on therapeutic efficacy. Neither age nor gender influenced the outcome. CONCLUSIONS: our results-obtained in a Central East European country-are in accordance with findings of suboptimal efficacy of traditional interferon monotherapy for chronic hepatitis C reported in the West, and suggest the benefit of the combination treatment of interferon with ribavirin.     

Clinical, enzymological and histological changes in chronic diffuse liver diseases following (+)-cyanidanol-3 (Catergen) treatment

The effect of (+)-cyanidanol-3 (Catergen) monotherapy was examined in 18 patients with alcoholic liver disease and in 12 patients with chronic active hepatitis. During the administration of the drug the majority of complaints diminished or ceased in both groups. In patients with alcoholic liver disease bromsulphalein retention and gamma glutamyl transferase levels decreased, in chronic active hepatitis serum glutaminic pyruvic acid transaminase (SGPT) and alkaline phosphatase levels increased, pseudocholinesterase level decreased. The histological abnormalities of alcoholic liver injury improved in the majority of cases, on the other hand, it was deteriorated in two third of the cases with chronic active hepatitis. In two cases the histological recovery of acute alcoholic hepatitis was observed. On the basis of this results we conclude that Catergen has an excellent therapeutic effect in alcoholic liver injury while in chronic active liver diseases it can be applied only as a part of combined therapy.     

恩替卡韦治疗45例慢性乙型重型病毒性肝炎的疗效观察

目的:评价恩替卡韦治疗慢性乙型重型病毒性肝炎的临床疗效。方法:45例患者在常规治疗的基础上给予恩替卡韦0.5mg,每日1次口服;另47例给予拉米夫定100mg,每日1次口服,存活患者的治疗时间不少于6个月。结果:恩替卡韦组临床疗效总有效率为80.0%,显著高于拉米夫定组总有效率66.0%(P<0.05);总胆红素(TBIL)和谷丙转氨酶(ALT)分别由治疗前的378.2±36.3umol/L和546.8±56.5 U/L降至146.5±35.4μmol/L和46.5±21.5U/L,凝血酶原活动度(PTA)由治疗前的32.5±5.8%升至59.5±16.8%,均较拉米夫定组改善明显(P<0.05);恩替卡韦组的HBeAg和HBV-DNA转阴率分别为71.4和66.7%,明显高于拉米夫定组的47.6%和45.2%(P<0.05)。病死率分别为6.7%和10.6%,无显著性差异(P>0.05)。结论:恩替卡韦治疗慢性乙型重型肝炎患者在临床疗效、肝功能改善和抑制病毒复制方面均优于拉米夫定治疗者。     

Interferon-based treatment of chronic hepatitis C

The treatment of patients with chronic hepatitis C has rapidly evolved in the past 10 years centered on the use of interferon alpha 2 as an antiviral and immunomodulatory agent against hepatitis C virus. Firstly used as a monotherapy associated with a deceiving long-term efficacy, interferon alpha was then combined with ribavirin, a nucleoside analog with large antiviral properties. Combination of both drugs dramatically improved the efficacy of treatment with 50% of patients reaching a sustained viral response, characterized by the final eradication of the virus from the infected individual. Surprisingly, this synergistic effect remains greatly unexplained. The third step consisted in the use of pegylated interferon in order to adapt its pharmacokinetics and to allow a better efficacy with a more tolerable dosing schedule: once weekly subcutaneous injection instead of thrice weekly. Pegylated interferon combined with ribavirin during 24-48 weeks of treatment is the current standard of care with nearly 60% of sustained virologic response, overall. Development of new forms of interferon alpha are on the way with promising preliminary results.     

老年慢性便秘患者社区干预治疗评价

目的:评价老年慢性便秘患者社区干预治疗的疗效。方法:将2010年3月-2011年4月我院门诊收治的62例老年便秘患者随机均分为两组,对照组给予常规药物治疗,研究组在对照组治疗基础上辅以社区干预治疗,治疗半年后观察两组患者疗效。结果:治疗半年后,两组临床症状均有改善,但较对照组,研究组改善更为显著P<0.05;对照组治疗有效率为67.74%,研究组有效率为90.32%,两组比较差异显著P<0.05。结论:老年慢性便秘患者在常规药物治疗基础上辅以社区干预治疗,疗效显著,为老年慢性便秘治疗的有效方法。     

内江地区慢性乙型肝炎患者的基因型及拉米夫定联合阿德福韦酯抗病毒治疗效果

目的 探讨内江地区慢性乙型肝炎患者的基因型及拉米夫定联合阿德福韦酯抗病毒的治疗效果。方法 将201例慢性乙型肝炎患者进行HBV基因型的测定,其中120例HBeAg（+）慢性乙型肝炎患者随机分为三组：A组、B组和C组,每组40例。A组给予拉米夫定(LAM)治疗;B组给予恩替卡韦(ETV)治疗;C组给予LAM联合阿德福韦酯(ADV)治疗,比较治疗情况。结果 201例慢性乙型肝炎患者中B型119例（59.2%）,C型68例（33.8%）,B/C混合型10例（5.0%）,未知型4例（2.0%）,各分型之间的性别、年龄差异无统计学意义（P＞0.05）。C型感染者HBeAg阳性率为86.8%,显著高于B型的51.3%（P＜0.05）。HBeAg（+）的3组患者治疗12、24和48周时,B组和C组患者的ALT复常率、HBV DNA阴转率及48周时的HBeAg血清转换率均显著高于A组（P＜0.05）;C组患者与B组比较差异无统计学意义（P＞0.05）。治疗期间均未见不良反应发生。C组患者（包括B型19例、C型21例）中B型的HBV DNA阴转率及HBeAg血清转换率显著高于C型（P＜0.05）。结论 地处西南方的内江地区慢性乙型肝炎患者主要以B型为主,C型次之,B型和C型共占93.0%,其他型别仅占较少部分。ETV方案或LAM联合ADV方案治疗HBeAg（+）慢性乙肝疗效优于LAM治疗。初始LAM联合ADV治疗基因B型HBeAg（+）慢性乙型肝炎疗效优于C型。     

Antisense therapy of hepatitis B virus infection

Chronic infection with the hepatitis B virus (HBV) is a major health problem worldwide. The only established therapy is interferon-a with an efficacy of only 30–40% in highly selected patients. The discovery of animal viruses closely related to the HBV has contributed to active research on antiviral therapy of chronic hepatitis B. The animal model tested and described in this article are Peking ducks infected with the duck hepatitis B virus (DHBV). Molecular therapeutic strategies aimed at blocking gene expression include antisense DNA. An antisense oligodeoxynucleotide directed against the 5′-region of the preS gene of DHBV inhibited viral replication and gene expression in vitro in primary duck hepatocytes and in vivo in Peking ducks. These results demonstrate the potential clinical use of antisense DNA as antiviral therapeutics.     

Therapeutic effect of (+)-cyanidanol-3 in toxic alcoholic liver disease and in chronic active hepatitis

(+)-Cyanidanol-3 is considered to have cytoprotective effect in toxic liver injury. A randomized clinical trial was carried out in alcoholic precirrhotic patients and in chronic active hepatitis with (+)-cyanidanol-3 versus placebo. The daily dose of the drug was 1.5-2.0 g for a one-year period. A: Toxic alcoholic precirrhotic liver disease: 38 patients were treated with (+)-cyanidanol-3, 36 with placebo. We found significant improvement in the subjective symptome like asthenia and anorexia, and in serum aspartate-transaminase (GOT) levels. However, it is possible that the improvement was in part due to abstinence from alcohol. B: Chronic active hepatitis: previously introduced continuous prednisolone therapy (10-15 mg/day) was combined with (+)-cyanidanol-3 in 13 patients and with placebo in 12 controls. The results showed a more favourable, but not significantly better response in patients receiving (+)-cyanidanol-3 versus placebo. We concluded that the drug might be of benefit in some cases with chronic active hepatitis as an adjunct to corticoid therapy.     

Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C

The life cycle of the hepatitis C virus (HCV) is closely related to host lipoprotein metabolism. Serum levels of lipid are associated with the response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, while single nucleotide polymorphisms (SNPs) around the human interleukin 28B (IL28B) gene locus and amino acid substitutions in the core region of the HCV have been reported to affect the efficacy of PEG-IFN/RBV therapy in chronic hepatitis with HCV genotype 1b infection. The aim of this study was to elucidate the relationship between serum lipid and factors that are able to predict the efficacy of PEG-IFN/RB therapy, with specific focus on apolipoprotein B-100 (apoB-100) in 148 subjects with chronic HCV G1b infection. Our results demonstrated that both the aa 70 substitution in the core region of the HCV and the rs8099917 SNP located proximal to the IL28B were independent factors in determining serum apoB-100 and low-density lipoprotein (LDL) cholesterol levels. A significant association was noted between higher levels of apoB-100 (P = 1.1 × 10(-3)) and LDL cholesterol (P = 0.02) and the subjects having Arg70. A significant association was also observed between subjects carrying the rs8099917 TT responder genotype and higher levels of apoB-100 (P = 6.4 × 10(-3)) and LDL cholesterol (P = 4.2 × 10(-3)). Our results suggest that apoB-100 and LDL cholesterol are markers of impaired cellular lipoprotein pathways and/or host endogenous interferon response to HCV in chronic HCV infection. In particular, serum apoB-100 concentration might be an informative marker for judging changes in HCV-associated intracellular lipoprotein metabolism in patients carrying the rs8099917 responder genotype.     

实时超声弹性成像对慢性乙肝并肝纤维化程度的诊断价值分析

目的:探讨实时超声弹性成像(real-time tissue elastograph,RTE)对慢性乙肝并肝纤维化的临床诊断价值。方法:选择慢性乙肝并肝纤维化患者100例,对患者进行RTE检查及肝病理穿刺检查,将RTE评分结果与病理结果进行对比分析。结果:随着肝脏纤维化S分期的不断增加,RTE评分结果亦逐渐升高,RTE评分结果与肝纤维化病理分期呈显著正相关(r=0.665,P0.01)。实时超声弹性成像诊断乙肝并肝纤维化的的敏感度为92,31%、特异度为86.36%、准确率为91%、阳性预测值为96.00%、阴性预测值为76.00%。结论:RTE作为一项无创检查技术,对慢性乙肝并肝纤维化具有较高的临床诊断价值。     

Interferon alfa with or without ribavirin for chronic hepatitis C: systematic review of randomised trials

ObjectiveTo assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C.DesignSystematic review of randomised trials on interferon alfa plus ribavirin combination therapy versus interferon alfa. Patients were naive (not previously treated with interferon), relapsers (transient response to previous interferon therapy), or non-responders (no response to previous interferon therapy).ResultsCompared with interferon, combination therapy reduced the risk of not having a sustained virological response for 6 months by 26% in naive patients (relative risk 0.74, 95% confidence interval 0.70 to 0.78), 33% in relapsers (0.67, 0.57 to 0.78), and 11% in non-responders (0.89, 0.83 to 0.96). Morbidity and mortality showed a non-significant trend in favour of combination therapy (Peto odds ratio 0.45, 0.19 to 1.06). Combination therapy significantly reduced the risk of not having improvement in results of histology by 17% in naive patients (0.83, 0.74 to 0.93) and by 27% in relapsers and non-responders (0.73, 0.66 to 0.82). The risk of treatment discontinuations was significantly higher after combination therapy (1.28, 1.07 to 1.52).ConclusionTreatment with interferon alfa plus ribavirin has a significant beneficial effect on the virological and histological responses of patients with chronic hepatitis C, irrespective of previous treatment. Combination therapy may therefore also be considered appropriate for relapsers and non-responders.

What is already known on this subject

Interferon alfa was the recommended treatment for chronic hepatitis C until the late 1990sCombination therapy is recommended for previously untreated patients with chronic hepatitis C, but the benefit of treating relapsers and non-responders to previous treatment with interferon remains controversialThe effect of treatment on liver related morbidity and mortality has not been established

What this study adds

Combination therapy is more effective in treating hepatitis C than interferon alfa alone in naive patients, relapsers, and non-respondersCombination therapy significantly reduced the risk of not having a sustained virological or histological response irrespective of previous treatment and may therefore also be considered in relapsers and non-responders to previous treatmentThe data indicate a non-significant trend towards a beneficial effect on morbidity plus mortality rates     

IL-1 beta attenuates IFN-alpha beta-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent pathway

IFN-alphabeta is the only established treatment for viral hepatitis; however, more than 60% of patients are poorly responsive. Because viral hepatitis is associated with inflammation, we hypothesized that inflammation may attenuate the efficacy of IFN therapy. To test this hypothesis, the effect of IL-1beta, one of the major proinflammatory cytokines, on IFN signaling pathway in the liver was examined. Administration of IL-1beta in vivo attenuated IFN-alphabeta-induced STAT1 tyrosine phosphorylation in the liver but not in the spleen. The inhibitory action of IL-1beta in vivo was not affected by depleting hepatic Kupffer cells, suggesting that IL-1beta may directly target IFN-alphabeta signaling in hepatocytes. Indeed, pretreatment of human hepatocellular carcinoma HepG2 cells with IL-1beta suppressed IFN-alphabeta-induced antiviral activity and antiviral protein MxA mRNA expression. Furthermore, IL-1beta attenuated IFN-alphabeta-induced STAT1 binding and tyrosine phosphorylation without affecting the level of STAT1 protein. This inhibitory effect can be reversed by pretreatment with either proteasome inhibitors or transfection of dominant negative NF-kappaB inducing kinase mutants. Taken together, these findings suggest that IL-1beta attenuates IFN-alphabeta-induced STAT1 activation by a proteasome-dependent mechanism. In view of high levels of IL-1beta in the serum or within the liver of patients with chronic liver diseases, attenuation of IFN-alphabeta signaling in the liver by IL-1beta could be one of the mechanisms underlying the resistance to IFN therapy in chronic hepatitis C, and IL-1beta could be a potential therapeutic target for improving the efficacy of IFN therapy.     

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.     

Trypanosoma brucei and T. vivax: salicylhydroxamic acid and glycerol treatment of acute and chronically infected rats

In rats infected with monomorphic Trypanosoma brucei brucei, the efficacy of the therapy with salicylhydroxamic acid plus glycerol, i.e., combined therapy, decreased with increasing time after infection. It failed completely after the infection was made chronic by suboptimal treatment for 6 weeks. When this chronic infection had been established and "optimal" treatment was given, viable trypanosomes could still be detected 1 day later in brain and muscle but not in blood. In most organs, the concentrations of salicylhydroxamic acid and glycerol were lower than in the blood plasma; the maximum concentration of glycerol in the brain was only 20% of that in plasma. The most likely explanation for the failure of the combined therapy is that, in certain tissues, the concentration of the drugs remains too low to kill extravascular trypanosomes. Other explanations, such as the selection of a resistant strain or the survival of (extravascular) forms with a more active mitochondrion, could be excluded with a high degree of probability. Suramin was very effective, even after combined therapy had failed repeatedly, while melarsoprol was less effective. As in combined therapy, the dose of melarsoprol that could cure an acute infection was insufficient to cure a chronic infection. Combined therapy failed after a spontaneous chronic infection with T. b. rhodesiense had existed for 5-7 weeks, but it was effective in T. vivax infected rats even when parasitemia had been present for at least 4 days. Effective alternative schedules for combined therapy were not found.     

Treatment of genotype 1b HCV-related chronic hepatitis: efficacy and toxicity of three different interferon alfa-2b/ribavirin combined regimens in naive patients

This prospective open-label randomized trial of chronic hepatitis C genotype-1b patients compared compared the efficacy and safety of peg-interferon alfa-2b administered once-weekly versus interferon alfa-2b thrice-weekly or daily, both in combination with ribavirin. Seventy-eight previously untreated patients, with biopsy-documented genotype 1 chronic HCV and persistently elevated ALT levels and detectable HCV RNA, were randomized (26 subjects each) to receive: interferon alfa-2b at 6MIUs.c./three-times-weekly (group A) or interferon alfa-2b, 3MIUs.c./daily (group B) or peg-interferon alfa-2b 1.5mcg/Kg s.c./once-weekly (group C). All regimens included standard weight-based doses of ribavirin (800, 1,000 or 1,200 mg/day) administered for 52-weeks. Patients in the three groups were comparable for age, sex, viral load, ALT value and histological-activity-index (HAI). Therapy was completed by 22, 20 and 23 patients in groups A, B and C, respectively. At the end of treatment, a complete (biochemical and virological) response was observed in 50.0% patients of group A, 57.7% of group B and 65.4% of group C. After an additional 24-weeks of follow-up, a sustained response was observed in 26.9%, 46.1% and 50.0% of patients in groups A, B or C, respectively. Therapy was discontinued by 4, 6 and 2 patients because of adverse events in the above three groups. In naive patients with chronic genotype-lb hepatitis C, a 48 week therapy with peg-interferon or interferon at daily doses combined with ribavirin were both more effective than treatment with thrice-weekly interferon in inducing end of treatment and sustained response. Peg-interferon treatment was better tolerated and provoked significantly fewer therapy discontinuations.     

Treatment of chronic hepatitis C

Chronic hepatitis C entails a life-long risk of developing cirrhosis and hepatocellular carcinoma and eradication of the hepatitis C virus (HCV) is the only realistic approach for lowering the risk of disease progression. Treatment is indicated for patients with high transaminases and histologic signs of chronic hepatitis: 6-12 month therapy with 3-6MU interferon alfa thrice weekly combined with 1-1.2 grams ribavirin yielded up to 30% sustained virological responses (SVR). SVR raised up to 50% with pegylated interferons combined with ribavirin. Favourable predictors of response to the former treatment are genotype 2 or 3, less than 2 million copies of HCV, no or portal fibrosis at biopsy, age less than 40 yr and female gender. The same was true for the latter treatment, however, with body weight less than 82 kg replacing female gender. Six month treatment is enough for treating genotype 2 or 3 patients whereas 12-month therapy is indicated for the more resistant patients with genotype 1 or 4.98% cure of community-acquired acute hepatitis C was achieved with early treatment with daily doses of 5MU interferon, compared to a calculated 30% virus clearance occurring in untreated patients. Cost-effective stopping rules based upon early clearance of serum HCV-RNA, are under investigation. A cut-off equal or more than 2 log decrease in serum HCV-RNA at week 12, has 97% negative predictive value and 60% positive predictive value. Treatment could be optimized also by retreatment with combination therapy of relapsers and non-responders to monotherapy, with SVR rates of 50% and 25%, respectively. Difficult-to-treat patients include patients who have high genotype 1 and 4 viremia or coinfection with HIV or hepatitis B virus as well as patients who carry an organ graft. Extended treatment of virological non responders with pegylated interferons might slow down progression of hepatic fibrosis and prevent hepatocellular carcinoma.