Cytokine production in patients with chronic viral hepatitis C during treatment with interferon-alpha

Serum content of proinflammatory cytokines (IL-1 beta, IL-6, TNF-alpha) and growth factors (GM-CSF, TGF-1 beta) and expression of CD14 and CD95 antigens on peripheral blood monocytes before and after 12-day therapy with alpha-interferon were studied in 25 patients with chronic viral hepatitis C (VHC). The concentrations of TNF alpha, GM-CSF, and TGF-1 beta were significantly increased (p < 0.05) and coexpression of CD14+ and CD95+ antigens on monocytes was increased by 61% in VHC patients in comparison with the control. After 3 months of therapy with alpha-interferon, the content of TNF alpha, GM-CSF, and TGF-1 beta essentially decreased and that of IL-6 increased; this was paralleled by improvement of clinical and laboratory parameters and decrease of coexpression of CD14+ and CD95+ antigens on blood monocytes. Modulation of the functions of immunocompetent cells and changed production of cytokines are apparently one of the mechanisms of inhibitory effect of alpha-interferon on HCV infection. Study of proinflammatory cytokines and growth factors in the serum and expression of CD14 and CD 95 antigens on monocytes can serve as additional tests for evaluating the efficiency of interferon therapy in patients with VHC.     

Cytokine spectrum in patients with chronic hepatitis C in the treatment with interferon-alpha drugs

AIM: To evaluate the trend in content of IL-1, 2, 4, 6, TNF-alpha, interferon-alpha (Inf-alpha) and gamma (Inf-g) in the serum of patients with chronic hepatitis C (CHC) in the course of treatment with Inf-alpha. MATERIAL AND METHODS: The study included 30 patients with CHC (20 males and 10 females) and 25 healthy controls. Markers of CHC were detected with enzyme immunoassay, RNA--with polymerase chain reaction. Index of histological activity was calculated for 20 patients. Immune response mediators were determined with enzyme immunoassay before therapy with intron A in a dose 3000000 U 3 times a week and after 12 weeks of such treatment. RESULTS: Before the treatment absolute levels of inflammation mediators were high, after 3 months of treatment RNA of VHC was absent in 16 (55%) of the patients, 18 (60%) had low activity of transaminases. In 6 months VHC-RNA was not detected in 8 (28%) patients. Patients with a persistent positive effect had Ifn-g significantly higher than in unstable effect. IL-4 showed an opposite trend. CONCLUSION: High concentrations of IL-4 and low of Ifn-g in the serum of CHC patients before If treatment determined high activity of Th-2 system mediators, active replication of HCV and worse response to therapy.     

犀泽汤治疗慢性乙型肝炎40例疗效观察

目的观察犀泽汤治疗慢性乙型肝炎湿热中阻证患者的疗效,探讨治疗慢性乙型肝炎的有效疗法。方法将80例中医辨证属湿热中阻证的慢性乙型肝炎患者随机分为对照组40例,治疗组40例。对照组在肝病常规治疗的基础上采用甘利欣治疗,每次150mg,1天3次,口服,3个月为1个疗程,治疗2个疗程。治疗组在肝病常规治疗的基础上采用犀泽汤随症加减治疗,每天1剂,水煎服,3个月为1个疗程,治疗2个疗程。结果治疗组在改善症状、恢复肝功能方面优于对照组（P〈0.001,P〈0.01,P〈0.05）,但两组患者的ALT的复常率近似。治疗6个月时,治疗组HBVDNA转阴率为7.5%,对照组为0;治疗组HbeAg转阴率及HBeAg血清转换率分别为11.54%,11.54%,对照组为4%及0。结论犀泽汤对慢性乙型肝炎湿热中阻证患者有一定疗效,对于不适合或不同意抗病毒治疗的慢性乙型肝炎患者不失为一种较好的治疗选择。     

替比夫定治疗e抗原阳性慢性乙型肝炎的疗效预测因素研究

目的探讨替比夫定酯治疗HBeAg（＋）慢性乙型肝炎的疗效预测指标,为个体化治疗提供依据。方法选取广州医学院第一附属医院HBeAg阳性慢性乙型肝炎患者60例,均予替比夫定600 mg治疗48周,检测治疗前及治疗后24、48周的HBsAg、HBeAg、HBV DNA定量及丙氨酸氨基转移酶（ALT）水平。根据治疗24周时血清HBV DNA水平,将患者分为两组,聚合酶链反应（PCR）低于检测下限（〈300拷贝/m l）的A组和高于检测下限（≥300拷贝/m l）的B组。结果治疗24周时HBV DNA水平越低,HBsAg下降幅度越大,在48周HBV DNA达到PCR检测不到的水平、HBeAg血清转换率和ALT复常率越高。A组患者在48周时HBeAg血清转换率为44.1%,B组患者则为8.3%,两组比较差异有统计学意义（χ2=22.1,P〈0.01）。结论乙型肝炎患者应用替比夫定治疗24周时HBV DNA水平及HBsAg下降幅度可作为48周疗效的预测指标。     

慢性丙型病毒性肝炎患者干扰素治疗后干扰素抗体的表达水平及其临床意义

目的：探讨慢性丙型病毒性肝炎（丙肝）患者干扰素治疗后干扰抗体的表达水平及其对干扰素治疗影响。方法：选择94例慢性丙肝患者采用a2b-IFN治疗，剂量为300mU/次，每周3次，3个月为1个疗程，共3个疗程，动态检测抗－HCV，HCV－RNA及a2b-IFN-IgG表达水平。结果a2b-IFN治疗后抗－HCV，HCV－RNA阴转率分别为32．98％（31／94）和38．30（36／94），常规治疗组治疗后抗－HCV，HCV0－RNA阴转率分别为10．00％（4／40）和15．00％（6／40），两者相比有显著性差异（P＜0．01），干扰素治疗后抗－IFN－IgG阳检率为5．32％（5／94），与常规治疗组相比无显著性差异（P＞0．05），其中第一，第二，第三疗程结束后，抗－IFN－IgG阳检率分别为0（0／94），2．13％（2／94）和5．32％（5／94），干扰素治疗中抗－IFN－IgG产生率无显著性差异（P＞0．05），结论：a2b－IFN对抗－HCV，HCV－RNA阴转具有肯定疗效，且优于常规治疗，其具有一定的免疫原性，在治疗过程中可诱导机体产生少量抗a2b-IFN-IgG，其对IFN－a2b的抑制作用较弱。     

血浆置换对慢性重型肝炎的疗效分析

目的探讨人工肝血浆置换治疗对慢性重型肝炎的临床疗效。方法选取我院肝病科行人工肝血浆置换治疗的慢性重型肝炎患者67例为研究对象,比较治疗前后患者血常规及肝功能等生化学指标的变化,评价血浆置换的疗效。结果 67例重型肝炎患者经过人工肝血浆置换治疗后,白细胞、肝功能、凝血功能等指标及临床症状均得到不同程度的改善。其中,白细胞、直接胆红素在治疗前后差异有统计学意义(t=2.42、2.51,P<0.05),且ALT、AST、PT以及总胆红素的差异尤为显著(t分别为3.58、2.97、4.23及5.25;P均<0.01)。慢性重型肝炎早、中、晚期治疗有效率(包括治愈和好转)分别为86%、57%、11%;早期、中期与晚期重型肝炎患者PE治疗相比,治疗有效率的差异有统计学意义(χ2=18.53,P<0.01)。结论应用人工肝血浆置换治疗慢性重型肝炎是目前比较成熟的肝脏替代疗法,具有一定疗效,尤其对早、中期的患者疗效更佳。     

耳穴磁珠贴压治疗慢性乙型肝炎肝郁气滞型失眠的疗效研究

目的探讨耳穴磁珠贴压治疗慢性乙型肝炎肝郁气滞型失眠的方法及临床疗效。方法将58例慢性乙型肝炎肝郁气滞型失眠症患者分为试验组和对照组。试验组30例在常规治疗的基础上加用耳穴磁珠贴压,对照组28例仅采用常规治疗。比较两组患者睡眠改善情况。结果干预后试验组SPIEGEL睡眠量表评分高于对照组(P<0.01)。结论耳穴磁珠贴压对慢性乙型肝炎肝郁气滞型失眠症有较好的临床疗效。     

Severe exacerbation of asthma: a new side effect of interferon-alpha in patients with asthma and chronic hepatitis C

Interferon-alpha is used by physicians to treat numerous common medical disorders; however, therapy is often limited by side effects. Pulmonary complications, such as interstitial pneumonitis and bronchiolitis obliterans organizing pneumonia, have been described in patients receiving interferon-alpha therapy. Exacerbation of asthma induced by subcutaneous administration of interferon-alpha has not been previously reported. We describe two patients with mild asthma in whom treatment with interferon-alpha for chronic hepatitis C resulted in exacerbation of the underlying asthma. The severe asthmatic symptoms resolved promptly after use of interferon-alpha was discontinued and corticosteroid therapy was initiated. Repeated treatment with interferon-alpha several months later resulted in a rapid, more severe exacerbation of asthma in both patients. Patients undergoing therapy with interferon-alpha, especially those with chronic asthma, should be monitored closely for pulmonary symptoms. If these symptoms develop, patients should be instructed to discontinue use of interferon-alpha and seek medical attention immediately.     

Investigation of oxidative stress and some antioxidants in patients with acute and chronic viral hepatitis B and the effect of interferon-alpha treatment

OBJECTIVE: The aim of the study was to determine oxidative stress in patients with acute and chronic viral hepatitis B. DESIGN AND METHODS: 23 (11 F, 12 M) healthy controls, 23 (8 F, 15 M) patients with acute viral hepatitis B (AVHB) and 25 (9 F, 16 M) patients with chronic viral hepatitis B (CVHB) were studied. Serum malondialdehyde (MDA), conjugated dienes (CD), ALT, AST, total and direct bilirubins, beta-carotene and whole blood reduced glutathione (GSH) levels of all subjects were measured. In patients with CVHB, these parameters were measured both before and 6 months after treatment with interferon-alpha (IFN-alpha). RESULTS: MDA, CD, ALT, AST and total and direct bilirubin levels of the patients with AVHB and CVHB before treatment were significantly higher (P<0.001) whereas GSH and beta-carotene levels were lower (P<0.001) than those of the controls. MDA, CD, GSH, beta-carotene, ALT, AST and total and direct bilirubin levels of the patients with CVHB returned approximately to normal levels 6 months after treatment with IFN-alpha. CONCLUSION: Our results clearly show that patients with AVHB and CVHB are under the influence of increased oxidative stress (MDA and CD were increased) associated with lower levels of some antioxidants (beta-carotene and GSH). These impairments return to normal levels after IFN-alpha treatment of CVHB patients. These findings suggest that antioxidant supplementation might be considered in patients with acute or chronic hepatitis B.     

Comparative efficacy of combined treatment with intron A and pegintron in combination with ribavirin of patients with chronic hepatitis C

AIM: To investigate the efficacy of combined therapy of patients with chronic hepatitis C (CHC) including intron A, pegintron (preparations of alpha-2b interferon) and ribavirin, and evaluation of the above treatment side effects. MATERIAL AND METHODS: 47 CHC patients (38 males and 9 females) were divided into two groups. 22 patients of group 1 received intron A and ribavirin, 25 patients of group 2 were given pegintron and ribavirin for 6-12 months. The examination made before the treatment, during the treatment and after it included clinical, biochemical, virusological blood tests, tests for autoantibodies, thyroid hormones, ultrasound investigation. RESULTS: The response in group 1 was 55%, in group 2--72.7%. In group 2, CNS and skin side effects occurred more frequently. After the treatment side effects regressed in 95.8% patients. CONCLUSION: The pilot experience in Russia confirmed the findings of the foreign investigators on higher efficacy of combined treatment with pegylized interferons (pegintron) and ribavirin vs combination of intron A with ribavirin. It is shown that side effects of the above treatment can be corrected in outpatient medication.     

Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy

Background

Mood and anxiety symptoms in chronic hepatitis C (CHC) may be related to the patient awareness of the diagnosis and prognosis, to side effects induced by interferon (IFN)-alpha treatment, as well as to substance abuse. However, the observation of metabolic alterations in patients with CHC has led to hypothesize a direct effect of hepatitis C virus (HCV) on brain function. This study was aimed at elucidating whether CHC is associated with specific anxiety or mood disorders independently of confounding factors.

Methods

Patient cohort: consecutive patients, 135 with CHC and 76 with chronic hepatitis B (CHB). Exclusion criteria: previous treatment with IFN-alpha, co-infection with HCV and hepatitis B virus, infection with human immunodeficiency virus, drug or alcohol abuse, or malignancies. Controls: subjects without evidence of hepatitis randomly extracted from the database of a previous epidemiological study; they were divided into two groups of 540 (332 males) and 304 (220 males) as controls for patients with CHC and CHB, respectively. The psychiatric diagnosis was formulated by means of the Composite International Diagnostic Interview Simplified carried out by a physician according to DSM-IV criteria.

Results

A higher lifetime prevalence of major depressive disorder (MDD) was observed among CHC compared to CHB or controls. The risk of MDD was not statistically different between CHB and controls. Both the CHC and CHB groups showed a significantly higher frequency of panic disorder when compared to controls. No statistical differences were observed in the prevalence of general anxiety disorder and social phobia when CHC or CHB were compared to controls.

Conclusion

The present study provides the first evidence of an association between CHC and MDD, diagnosed on the basis of well-defined international criteria. This association is independent of treatment with IFN-alpha and is not influenced by substance or alcohol abuse. By contrast, anxiety disorders do not appear to be specifically associated with CHC.

     

Effects of human leucocyte interferon on hepatitis B virus replication and immune responses in patients with chronic hepatitis B infection.

Eight patients with chronic hepatitis B infection (seven with chronic active hepatitis and one with chronic persistent hepatitis) were treated with daily intramuscular injections of human leucocyte interferon for periods of 5 to 8 weeks and in one case for 5 months. In one patient there was a marked fall in virus-associated DNA polymerase activity and in the number of DNA containing viral particles during each of two courses of interferon. Hepatitis Be antigen (HBeAg) also disappeared, the aspartate transaminase levels fell and liver histology improved. In the four other patients with detectable DNA polymerase activity there was an early fall but this was transient and in one of these patients there was a continuing rise in activity despite treatment. One other patient became HBeAg negative but hepatitis B surface antigen (HBsAg) titres were mostly unaffected by treatment. A marked decrease in T-lymphocyte mediated cytotoxicity towards HBsAg coated target cells was demonstrated and raises the possibility that an immunosuppressant action of interferon may offsets its direct anti-viral action but may also account for the improvement in liver function which occurred in some patients.     

Prolonged lamivudine treatment in patients with chronic active anti-HBe-positive hepatitis

The efficacy of lamivudine (LAM) at 100 mg/d for 1 year in normalizing serum ALT levels and suppressing HBV DNA has been demonstrated in many studies. However, frequent relapses make long-term results modest. In the present study, we evaluated the efficacy of LAM administered for 3 years in patients with chronic active anti-HBe-positive hepatitis. Thirty-four patients with chronic active anti-HBe-positive hepatitis were treated with LAM (100 mg) once daily for 3 years. Before treatment, all patients demonstrated serum ALT levels >2 times normal levels for >6 months and HBV DNA positivity >5 pg/mL as determined by the sandwich hybridization test for nucleic acid. Both ALT and HBV DNA were monitored during therapy. After 12 months of therapy, 24 of 34 patients (70.6%) showed evidence of HBV DNA clearance and normal ALT levels; 22 of 34 (64.7%) and 19 of 34 (55.8%) patients maintained a complete response after 2 and 3 years of therapy, respectively. The long-term LAM therapy (>1 year) was not associated with an increase in the response of intially nonresponder patients. The YMDD variant emerged in 17.6% of patients in the first year, in 35.2% during the second year, and 52.9% during the third year of treatment. LAM was well tolerated during the 3-year therapy in all patients. Patients with chronic active anti-HBe-positive hepatitis demonstrated that the LAM response rate tends to decrease over time due to the emergence of YMDD variants.     

Modelling of early viral kinetics and pegylated interferon-alpha2b pharmacokinetics in patients with HBeag-positive chronic hepatitis B

BACKGROUND: Pegylated interferon alpha2b (PEG-IFN-alpha(2b) is effective for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, although its mechanism of action remains unclear. HBeAg loss is achieved in 36% of patients after one year of PEG-IFN-alpha2b treatment and combination therapy with lamivudine is not superior to PEG-IFN-alpha2b monotherapy. METHODS: Early pharmacokinetics and viral kinetics were analysed in patients treated for 52 weeks with PEG-IFN-alpha2b with or without lamivudine. RESULTS: After 4 weeks of treatment, there was a median viral decline of 2.94 log10 copies/ml in those treated with PEG-IFN-alpha2b and lamivudine and only 0.45 log10 copies/ml in the PEG-IFN-alpha2b monotherapy group. Peak PEG-IFN-alpha2b levels were reached approximately one day after administration and subsequently declined exponentially, consistent with a viral load rebound near to baseline levels at the end of the dosing period in most patients receiving PEG-IFN-alpha2b monotherapy. Modelling of pharmacokinetics and viral kinetics data in this group revealed that viral load was minimal 3.6 days after PEG-IFN-alpha2b administration, the mean maximal and mean antiviral effectiveness was 70% and 48% with a mean infected cell loss rate of 0.07 per day, while no significant biphasic decline was observed. CONCLUSIONS: PEG-IFN-alpha2b induces a sustained response in a considerable number of patients despite limited direct antiviral activity during the first weeks of antiviral therapy.     

Defective synthesis of granulocyte-colony stimulating factor in pegylated interferon-alpha treated chronic hepatitis C patients with declining leukocyte counts

BACKGROUND: Pegylated-interferon-alpha (peg-IFN-alpha) is the mainstay of treatment for chronic hepatitis C (CHC). Treatment is often complicated by neutropaenia due to inhibition of haematopoiesis. However, there are no data on the kinetics of granulocyte-colony stimulating factor (G-CSF), a major neutrophil growth factor, in this setting. We therefore evaluated G-CSF synthesis in CHC patients on peg-IFN-alpha treatment. METHODS: A total of 40 CHC patients were studied. None had pre-existing haematological disorders, or hepatitis B virus or HIV coinfection. For controls, 30 healthy subjects were used. Laboratory examinations, including liver function tests, were performed at baseline and monthly over treatment and follow-up. Serum G-CSF was measured in all patients and controls at baseline and in a subgroup of 20 CHC patients also at weeks 2, 4, 24, 48 and 72 after treatment start. RESULTS: CHC patients had a significantly lower pre-treatment neutrophil count (3,256 +/- 1,197 versus 3,804 +/- 859; P = 0.03). Notwithstanding, they showed lower baseline G-CSF serum levels than healthy controls (16.1 +/- 6.2 versus 19.4 +/- 7.5; P = 0.048). Consistently, baseline G-CSF levels were poorly correlated with the neutrophil count in CHC patients (r = -0.2; P = 0.2). Moreover, serum G-CSF levels did not increase in any of the 20 CHC patients during peg-IFN-alpha treatment, despite declining neutrophil counts. CONCLUSIONS: The lower neutrophil counts observed in CHC might be related to an absolute deficiency in G-CSF production. In the human model of neutropaenia induced by peg-IFN-alpha, we show that endogenous G-CSF levels are not physiologically up-regulated to overcome the decline in neutrophil counts. Our study provides a rationale for the evaluation of recombinant human G-CSF treatment in peg-IFN-alpha-induced neutropaenia.     

New drugs of treatment of patients with chronic hepatitis B

There are five approved drugs for the treatment of chronic hepatitis B(lamivudine, adefovir dipivoxil [ADV], entecavir [ETV], as well as pegylated and standard interferon) in Japan. In this paper, the reported data of new four drugs(tenofovir disoproxil fumarate [TDF], telbivudine, emtricitabine [FTC], clevudine) were described. TDF demonstrated potent antiviral efficacy in naive patients. Moreover, TDF is efficacious in lamivudine- or ADV-refractory patients. TDF monotherapy and the combination of FTC and TDF had similar efficacy in patients with incomplete viral suppression after therapy with ADV; response was not influenced by the presence of baseline lamivudine- or ADV-associated mutations.     

A prospective comparison of the effect of interferon-alpha and interferon-beta treatment in patients with chronic hepatitis C on the incidence of hepatocellular carcinoma development

To investigate differences in the effect of interferon (IFN) -alpha and IFN-beta treatment for hepatitis C on hepatocellular carcinoma (HCC) development, we prospectively followed 351 consecutive patients (median age, 56.6 years; mean follow-up, 5.7 ± 2.6 years) with chronic hepatitis C virus (HCV) viremia. Of 260 IFN-alpha and 91 IFN-beta treated patients, 17 (6.5%) and 4 (4.4%), respectively, developed HCC. Virological response (VR) was defined as persistent HCV RNA disappearance from serum, and biochemical response (BR) as persistent alanine aminotransferase (ALT) normalization after treatment. No significant between-group differences in HCC development were found between those with and without VR. Although the HCC development rate in patients without BR was significantly higher than that in patients with BR in the IFN-alpha group (11.4% and 0.8%; P 0.05), no significant difference was found in the IFN-beta group (6.3% and 2.3%). Similar rates of HCC development were found in patients with chronic HCV viremia treated with either IFN-alpha or IFN-beta.