Side-effects of pegylated interferon plus ribavirin therapy with or without protease inhibitor direct acting antiviral agents during treatment of chronic hepatitis C virus infection

Hepatitis C virus (HCV) infection affects 2-3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-na?ve patients infected with HCV genotype G1, and only 15-20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10-15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts - with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients.     

Hungarian consensus guideline for the diagnosis and treatment of B, C, and D viral hepatitis

More than 1% of the Hungarian population is infected with hepatitis B, C, or D viruses. Since 2006 the diagnostics and therapy of these infections are carried out in treatment centers according to national guidelines - since 2010 according to financial protocols. The consensus-based guidelines for 2012 are published in this paper. The guidelines stress the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection is pegylated interferon for 48 weeks or continuous entecavir therapy. The later must be continued for at least 6 months after hepatitis B surface antigen (HBsAg) seroconversion. Tenofovir disoproxil fumarat is not yet reimbursed by the National Health Insurance Fund. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Treatment naive chronic hepatitis C patients should initially receive pegylated interferon and ribavirin dual combination therapy. In genotype 1 infection if response is insufficient at 4 or 12 weeks one of the two new direct acting antivirals (boceprevir or telaprevir) should be added. The length of treatment is usually 48 weeks; in cases of extended early viral response shorter courses are recommended. Previous treatment failure patients with genotype 1 infection should receive a protease inhibitor backed triple combination therapy, mostly for 48 weeks. However, relapsers without cirrhosis and with extended rapid viral response, shorter telaprevir based combination therapy is sufficient. Drug-drug interactions as well as emergence of viral resistance are of particular importance. For genotype 2 or 3 HCV infections 24 weeks, for genotype 4 infections 24, 48 or 72 weeks of pegylated interferon plus ribavirin therapy is recommended in general. The guidelines published here become protocols when published as official publications of the Hungarian Health Authority.     

Is Response-Guided Therapy Being Applied in the Clinical Setting? The Hepatitis C Example

Background

Response-guided therapy (RGT) is a treatment model that bases adjustments to therapeutic regimens on individualized patient physiologic response. This approach is applied to patients with chronic hepatitis C virus (HCV) infection who are treated with a triple therapy regimen of boceprevir or telaprevir in combination with pegylated interferon and ribavirin. As RGT expands in other pharmacologic regimens, including the treatment of breast cancer and acute myeloid leukemia, a measurement of how this approach is applied in clinical practice is important to determine whether the benefits of RGT are being optimized.

Objective

To measure adherence to the RGT guidelines and to the treatment futility rules based on the drug labeling information for boceprevir and for telaprevir in the treatment of patients with chronic HCV infection.

Methods

A retrospective observational cohort study was conducted using the large Humana research database, which includes pharmacy, medical, and laboratory claims, as well as enrollment data for more than 1.5 million fully insured commercial members, 1.9 million Medicare Advantage members, and 2.4 million Medicare Part D members from all 50 states. The study population included patients aged ≥18 years to <90 years who were fully insured with commercial or Medicare Advantage coverage. A pharmacy claim for boceprevir or telaprevir was used to identify patients receiving triple therapy for HCV infection. Medical, pharmacy, and laboratory claims were reviewed from the date of the first boceprevir or telaprevir pharmacy claim between May 2011 and February 2012 through a 32-week follow-up period, during which patients were required to have continuous health plan enrollment eligibility. This time period allowed for the occurrences of required HCV RNA laboratory monitoring and the assessment of treatment patterns. The use of RGT for boceprevir and telaprevir includes the monitoring of HCV RNA levels at routine intervals to determine how to proceed with therapy. Adherence to HCV RNA monitoring was measured as the proportion of eligible patients who had an HCV RNA assay at each of the recommended time intervals. According to futility rules, patients with greater-than-expected HCV RNA levels are deemed to be nonresponders and should discontinue therapy. Adherence to futility rules was measured as the proportion of patients who stopped therapy among all patients who had an HCV RNA result, which indicated treatment futility at each monitoring interval.

Results

A total of 326 patients (65 in the boceprevir group; 261 in the telaprevir group) were eligible for the HCV RNA monitoring analysis, and 134 patients (20 receiving boceprevir and 114 receiving telaprevir) were eligible for the futility rules analysis. There were 1203 HCV RNA assays during the follow-up period. The percentage of patients who were adherent to HCV RNA monitoring during the entire treatment period was 29.2% in the boceprevir group and 32.2% in the telaprevir group. In both treatment groups, adherence to HCV RNA monitoring was highest at the first recommended time interval, followed by a downward trend in the second and third time intervals. Approximately 15% of 134 eligible patients met the futility rules for stopping therapy based on HCV RNA assay results, and 55% of those patients stopped the therapy in accordance with the treatment futility rules.

Conclusion

The implementation of RGT was suboptimal in this population of patients with chronic HCV infection; adherence to HCV RNA monitoring guidelines was less than 33%, and adherence to treatment futility rules was less than 50%. Managed care pharmacists should identify strategies to increase the adoption of RGT, which may, in turn, improve patient care and reduce unnecessary expenditures.     

Treatment of hepatitis C: Perspectives

The treatment of hepatitis C virus (HCV) infection has significantly improved in the last 2 decades. The association of pegylated interferon alfa and ribavirin (PR) has allowed a sustained virologic response (SVR) for nearly 15 years i.e. a viral cure of the infection for 45% of genotype 1-, 65% of genotype 4-, 70% of genotype 3- and around 85% of genotype 2-infected patients. A better understanding of the HCV life cycle has led to the development of direct-acting antiviral drugs (DAAs) targeted against viral proteins (NS3/4A protease, NS5B polymerase with nucleotide and non-nucleotide inhibitors, NS5A viral replication complex). The combination of first-generation protease inhibitors with PR demonstrated a high antiviral effectiveness (75% of SVR but restricted to genotypes 1) with substantial adverse effects for the first-generation protease inhibitors, which obtained market approval in 2011 (telaprevir and boceprevir), recommendations for use in HCV monoinfected patients in 2012, and in HCV/HIV coinfected in 2013. Then, the combination of second-generation protease inhibitors with PR increased SVR rates from 75 to 90%, while reducing treatment duration, adverse effects, and the number of pills. The next step will be using an interferon and ribavirin-free combination of DAAs; it should become the standard of care in 2015. These excellent results in “easy-to-treat” patients and in small populations in the first studies were confirmed in phase III studies and in “difficult-to-treat” patients (treatment – especially protease inhibitors – previously treated patients, cirrhotic patients, liver and renal transplant patients, HIV coinfected patients, and multi-drug treated patients, at increased risk of drug interaction). The high antiviral potency of these new combinations has changed the definition of “difficult-to-treat patients”. These unique achievements in drug history make any previous publication on hepatitis C treatment obsolete.     

Hepatitis C virus infection management in 2012

Hepatitis C virus (HCV) is the most common infectious cause of chronic liver disease in Europe. With the introduction of interferon based therapy in combination with ribavirin treatment of chronic HCV has become feasible. This therapy has become the standard of care for patients with HCV and depending on the HCV genotype treatment is successful in 40-70% of patients. In the recent years a new class of drugs have emerged that changed the landscape of HCV treatment. These direct antiviral agents inhibit the NS3/N4A serine protease of HCV. Prototypes are telaprevir and boceprevir and they specifically exert antiviral activity against genotype 1 HCV. A series of landmark trials has paved the way for introduction of these agents, and they have documented a great improvement in the care of genotype 1 HCV patients. Telaprevir and boceprevir are given in combination with pegylated interferon and ribavirin and are useful for treatment naive as well as treatment experienced patients. The clinician should be aware of these developments as they have implications for side effect management, and drug-drug interactions. Finally, strategic use of these agents comes with stopping rules and require close monitoring of the HCV viral load.     

Therapeutic vaccines against hepatitis C virus

Hepatitis C virus (HCV) is a blood-borne pathogen which has chronically infected about 130–210 million people worldwide. Current standard-of-care (SoC) therapy is an inadequate and expensive treatment with more side effects. Two direct-acting antiviral agents (DAAs) (telaprevir and boceprevir) in combination with SoC therapy have been used in patients infected with HCV genotype 1. Although these drugs result in a shortening of therapy, they also have additional side effects and are expensive. In their stead, several second-generation DAAs are being investigated. What important is that all-oral, interferon (IFN)- and ribavirin-free regimens for the treatment of HCV-infected patients are now being investigated, and will be applied in the next year. Preventive measures against HCV, including vaccine development, are also now in progress. However, no therapeutic vaccine against HCV has been produced to date. An effective vaccine should induce robust and broadly cross-reactive CD4⁺, CD8⁺T-cell and neutralising antibody (NAb) responses. Current data indicate that vaccines can usually not completely prevent HCV infection but rather prevent the progression of HCV infection to chronic and persistent infection, which may be a realistic goal. This review discusses the important roles of NAbs and CD8⁺T-cells in the development of therapeutic vaccines, and summarizes some important epitopes of HCV recognized by CD8⁺T-cells and some prospective therapeutic vaccine approaches.     

Interferon therapy of chronic viral hepatitis in Hungary: 5-year experience. A multicenter study]

In Hungary over the past 5 years more than thousand patients with chronic viral hepatitis have been examined and included in a treatment program with interferon (IFN) at 16 major hepatology centers, using unified diagnostic and therapeutical criteria. Authors give an account of their experiences on the clinical features of patients with chronic viral hepatitis and report the results of the treatment with IFN. According to the rules and availability of IFN for patients with chronic viral hepatitis in the country, virtually the entire Hungarian population with this diseases who required IFN therapy have been included. A total of 94 patients suffered from hepatitis B virus (HBV) infection, in addition 11 HBV + hepatitis Delta virus (HDV), 24 HBV + Hepatitis C virus (HCV) related liver disease, and 993 had chronic hepatitis C. IFN therapy for chronic HBV hepatitis consisted of IFN 5 MU thrice weekly for 6 months, and resulted in 33% seroconversion and sustained remission with 14% HBsAg clearance. For chronic hepatitis C treatment protocols (dose of IFN and duration of therapy) have changed with the time (from a weekly dose of 3 x 3 MU IFN for 6 months, to 3 x 3 MU for 12 months), and even a combination with ribavirin has been introduced. Although the therapeutic results showed a gradual improvement form a 13% sustained response over 22% in the first and second periods, respectively, differences were most significant with the advent of the combination therapy, that resulted in 36% remission rate. Only fibrosis in histology and baseline pretreatment HCV-RNA level appeared as predictors of response in chronic hepatitis C. Neither age nor gender did influence the outcome, but longer duration of treatment and higher total dose of IFN resulted moderately higher sustained remission rates. The experiences are in accordance with findings of suboptimal efficacy of IFN monotherapy reported worldwide and emphasize the need of seeking for newer and combination therapeutic modalities for these chronic viral diseases.     

Critical overview and outlook: pathogenesis, prevention, and treatment of hepatitis and hepatocarcinoma caused by hepatitis B virus

Viral hepatitis B is an enigmatic disease in which the host's own immune response to persistent viral infection may bring about host destruction through antiviral inflammatory responses which might otherwise present as a benign or inapparent disease. The simple solution to the hepatitis B problem is by immunoprophylaxis using the vaccine licensed in 1981, which prevents both infection and the late sequelae of liver cirrhosis and hepatocarcinoma. Immunotherapeutic vaccines against persistent hepatitis B infection have not been successful and new explorations are being directed to therapies which include antisense, ribozymes, gene silencing by RNA interference (RNAi) and aptamer approaches. Limited benefits from nucleoside therapy and limitations in opportunity for liver transplantation have left a large void of curative treatments. Findings with respect to e antigen tolerance provide a basis for exploration to determine whether passively administered e antigen might suppress cell-mediated immunity, creating a commensal state in which virus persists but without pathologic damage to the host. Therapy of hepatocarcinoma by conventional chemotherapy, radiation, or surgical resection and ablation gives little hope for restoration of health unless the tumor is detected very early. The large engagement of the world medical science community to develop therapeutic vaccines against cancer is now in major clinical trials to determine the hope and credibility for the immunization approach. Vaccines based on tumor peptides which are linked to heat shock proteins and directed to host dendritic cells give reason for excitement and may be the "best show in town". A new era of tumor therapy will need to be based on new discoveries in immune function which are required to pursue immunotherapy on a more rational basis. The many facets of current hepatitis B virology, pathogenesis, immunoprophylaxis, immunotherapeusis, chemotherapy, and tumor pathogenesis and therapy are discussed here, in depth, but in keeping with needed brevity.     

Improved hepatitis C treatment response in younger patients: findings from the UK HCV National Register cohort study

In a cohort of 272 treatment-naive individuals with chronic hepatitis C infection acquired on a known date who were enrolled in the UK HCV National Register, a progressive improvement in response to treatment was found with the evolution of antiviral therapies from 20% (25/122) for interferon monotherapy to 63% (55/88) for pegylated interferon+ribavirin therapy. Multivariable analysis results showed increasing age to be associated with poorer response to therapy [odds ratio (OR) 0·84, 95% confidence interval (CI) 0·72-0·99, P=0·03] whereas time since infection was not associated with response (OR 0·93, 95% CI 0·44-1·98, P=0·85). Other factors significantly associated with a positive response were non-type 1 genotype (P<0·0001) and combination therapies (P<0·0001). During the first two decades of chronic HCV infection, treatment at a younger age was found to be more influential in achieving a sustained viral response than treating earlier in the course of infection.     

病毒性肝炎患者血清甲状腺激素检测的临床意义

目的研究病毒性肝炎患者肝功能损害程度与甲状腺激素水平变化的相关性及其临床意义。方法采用化学发光法、酶法和凝固法分别测定病毒性肝炎患者和体检健康者血清T3、T4、FT3、FT4、TSH以及ALT、AST、TBIL、ALB、凝血酶原活动度等,并将肝炎患者进行分组,然后对实验结果进行分析比较。结果轻度肝病患者T3、FT4和中度肝病患者T3、T4均高于健康对照组（P〈0.05）;而重度肝病患者血清T3、FT3水平较轻度和中度患者降低（P〈0.05）;黄疸性慢性肝炎患者血清T3,T4,FT3和TSH水平明显低于非黄疸性慢性肝炎患者（P〈0.01）,慢性肝炎患者血清T3、T4明显高于肝硬化患者（P〈0.05）;另外,肝病患者中好转组T3,T4,FT3,TSH的水平均高于非好转组（P〈0.05）。结论病毒性肝炎患者肝功能的损害程度与其甲状腺激素水平的变化明显相关,肝病患者甲状腺激素水平的监测对肝功能受损导致甲状腺功能紊乱的临床诊治及疗效观察具有重要的实用价值。     

Hepatitis C infection: a review

Hepatitis C, transmitted through body fluid exchange, affects approximately 1.8% of the U.S. population, roughly 3.9 million persons. Transfusion of blood and blood products was once an important source of hepatitis C transmission. Since the initiation of the hepatitis C screening program in 1985, however, injection drug use has become a major route. Hepatitis C is a leading cause of chronic liver disease. In 80% to 85% of those infected with the virus, chronic hepatitis C eventually develops, which can lead to cirrhosis and hepatocellular carcinoma, with alcohol abuse and coinfection with hepatitis B as additional risk factors. Screening for hepatitis C can be achieved with serologic assays. Molecular assays are helpful in confirming the diagnosis, assessing viral load, and characterizing the genetic nature of the viruses. Interferon alpha (IFN-alpha) and a combination of IFN-alpha 2B and ribavirin are therapies available in treatment of hepatitis C, but sustained response to the treatment has been unsatisfactory. Further studies are indicated to obtain more effective therapies for eradication of the disease. Hepatitis C is preventable, and clinicians should use every opportunity possible in their practice to assess those at risk and actively engage them in risk factor reductions.     

Interaction of alcohol and hepatitis viral proteins: implication in synergistic effect of alcohol drinking and viral hepatitis on liver injury.

Alcohol drinking and viral hepatitis are both recognized as major causes of liver disease worldwide, and they frequently coexist and synergistically cause liver injury in patients with chronic liver disease. Several mechanisms have been implicated in exacerbation of liver injury in patients with alcohol drinking and viral hepatitis. These include impairment of host defense and liver regeneration by alcohol consumption. The findings obtained from my laboratory have demonstrated that alcohol potentiates cooperatively several signals activated by hepatitis B virus X protein (HBX) or hepatitis C virus core protein, and HBX sensitizes hepatocytes to tumor necrosis factor-alpha (TNF-alpha)- and ethanol-induced apoptosis by a caspase-3-dependent mechanism, which may also contribute to the synergistic effect of alcohol drinking and viral hepatitis on liver injury.     

Prevalence of chronic viral hepatitis in drug abusers

Authors examined the prevalence of hepatitis B, C and D viral infections in Hungarian drug users. Between January 1995 and October 1998 256 examinations were made (58% intravenous, 42% non intravenous drug user). Hepatitis C virus infection in 27 patients, hepatitis C and B virus infection in 4 patients, hepatitis B virus infection in 17 patients was detected. Every hepatitis B virus positive case was past infection. Hepatitis D virus infection was not detected. Clinically overt liver disease was proved in more than half of the hepatitis C virus infected patients. Because of insufficient collaboration only 11 were followed up. Liver biopsy was made in 5 cases. Interferon therapy was indicated in 3 cases. The 24% of intravenous drug users was anti-HCV seropositive contrary to 1.4% of non intravenous group. Anti-HCV seropositivity was proved in 38% in common needle users, while in disposable needle users only 3%. The prevalence of hepatitis C virus infection in intravenous drug users is rather frequent in Hungary too. The exact diagnosis of liver diseases is very difficult as for insufficient collaboration. The prevalence of hepatitis B virus infection in i.v. and non i.v. drug users is the same as in the normal population. The importance of information, especially to avoid common needle use is stressed.     

Antioxidant therapy in chronic liver diseases

In chronic liver diseases with inflammatory reactions (chronic viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, chemicals and drug induced hepatitis, Wilson disease, haemochromatosis) the oxidative stress, the cell alteration induced by free radicals is an important part of the pathogeneis beside the aetiological factors. In this paper the development of free radicals and their physiological role are demonstrated. The factors, which are influenced by the free radicals and antioxidants, as well as the pathological effects caused by oxidative stress in biological systems are discussed in details. The authors demonstrate the free radical processes as key factors in alcoholic liver diseases and non-acoholic steatohepatitis, furthermore the possible treatment modalities in the inhibition of these alterations. Also the free radical processes in chronic viral hepatitis and autoimmune hepatitis are discussed as well. The oxidative stress is able to enhance the progression of chronic inflammatory liver disease independently from the aetiological factor or with it together. That is why the antioxidant drugs could be applied also in the treatment of chronic liver diseases beside the therapy based on the aetiological factors.     

Cost-Effectiveness Analysis of Boceprevir for the Treatment of Chronic Hepatitis C Virus Genotype 1 Infection in Portugal

Background

The recent approval of two protease inhibitors, boceprevir and telaprevir, is likely to change the management of chronic hepatitis C virus (HCV) genotype 1 infection.

Objectives

We evaluated the long-term clinical outcomes and the cost effectiveness of therapeutic strategies using boceprevir with peginterferon plus ribavirin (PR) in comparison with PR alone for treating HCV genotype 1 infection in Portugal.

Methods

A Markov model was developed to project the expected lifetime costs and quality-adjusted life-years (QALYs) associated with PR alone and the treatment strategies outlined by the European Medicines Agency in the boceprevir summary of product characteristics. The boceprevir-based therapeutic strategies differ according to whether or not the patient was previously treated and whether or not the patient had compensated cirrhosis. The model simulated the experience of a series of cohorts of chronically HCV-infected patients (each defined by age, sex, race and fibrosis score). All treatment-related inputs were obtained from boceprevir clinical trials – SPRINT-2, RESPOND-2 and PROVIDE. Estimates of the natural history parameters and health state utilities were based on published studies. Portugal-specific annual direct costs of HCV health states were estimated by convening a panel of experts to derive health state resource use and multiplying the results by national unit costs. The model was developed from a healthcare system perspective with a timeframe corresponding to the remaining duration of the patients’ lifetimes. Both future costs and QALYs were discounted at 5 %. To test the robustness of the conclusions, we conducted deterministic and probabilistic sensitivity analyses.

Results

In comparison with the treatment with PR alone, boceprevir-based regimens were projected to reduce the lifetime incidence of advanced liver disease, liver transplantation, and liver-related death by 45–51 % and increase life expectancy by 2.3–4.3 years. Although the addition of BOC increased treatment costs by €13,300–€19,700, the reduction of disease burden resulted in a decrease of €5,400–€9,000 in discounted health state costs and an increase of 0.68–1.23 in discounted QALYs per patient. The incremental cost-effectiveness ratios of the boceprevir-based regimens compared with PR among previously untreated and previously treated patients were €11,600/QALY and €8,700/QALY, respectively. The results were most sensitive to variations in sustained virologic response rates, discount rates and age at treatment.

Conclusions

Adding boceprevir to PR was projected to reduce the number of liver complications and liver-related deaths, and to be cost effective in treating both previously untreated and treated patients.     

Analyse der Immunantwort bei Hepatitis C

The outcome of Hepatitis C virus infection depends on the interaction of the hosts immune system, particularly the virus specific T cell response, with the virus. An early vigorous multispecific TH1 lymphokine dominated and persistant CD4+ and CD8+ T cell response is associated with elimination (control) of the virus and self limited acute hepatitis C, whereas an absent or weak T cell response is associated with viral persistence and chronic course of disease. The weak immune response during chronic hepatitis C is insufficient to eradicate the virus, at best it may exert a certain control but on the other hand contributes to chronic liver damage. The role of the humoral immune response is not clearly defined yet. Understanding the HCV specific T cell response is of great importance since it paves the way for novel therapeutic and prophylactic vaccine approaches for this devastating disease.     

AFU、PT、Cp、T4联合检测在乙型肝炎患者中的临床意义

目的探讨乙型肝炎患者血清甲状腺素（T4）、铜蓝蛋白（Cp）、α-L-岩藻糖苷酶（AFU）和凝血酶原时间（PT）水平变化与肝功能损害程度的相关性及其临床意义。方法187病例分成慢性肝炎组、重型肝炎组和肝硬化组,同时选择同期进行体检的健康人作为对照组,分别检测T4、Cp、AFU和PT,并进行统计学分析。结果各病例组AFU、PT和T4与正常对照组比较,差异均具有统计学意义（P＜0．05）;肝硬化组AFU明显低于其他两个病例组（P＜O．01）;各病例组PT之间差异均具有统计学意义（P＜0．05）;慢性肝炎组T。高于其他病例组（P＜0．05）;重型肝炎组cp低于正常对照组及其他病例组（P＜0．05）,但慢性肝炎组和肝硬化组cp与正常对照组之间无显著性差异（P＞0．05）。结论联合检测T4,Cp,ALT和PT对病毒性肝炎的早期和鉴别诊断、病情判断以及疗效和预后评估有重要参考价值。     

流行性出血热灭活疫苗对慢乙肝HBV抑制的疗效初步观察

目的观察流行性出血热灭活疫苗对慢乙肝ＨＢＶ抑制的临床疗效。方法选择符合病毒性肝炎防治方案（试行）诊断标准的病例共５００例，其中乙肝病毒携带者治疗组１５７例，慢乙肝治疗组２９３例，乙肝后肝硬化治疗组５０例，并设慢乙肝干扰素治疗对照组３０例。各治疗组均以流行性出血热灭活疫苗肌注，治疗中每周检测血尿常规，每半月测肝、肾功能，每月测乙肝三系（ＥＬＩＳＡ）与ＨＢＶ－ＤＮＡ（ＰＣＲ），并记录疫苗不良反应。结果各治疗组的即刻完全应答率均高于对照组的阴转应答率。慢乙肝疫苗治疗组即刻完全应答率（３４．４％）低于慢乙肝干扰素治疗的对照组（４０．０％）（Ｐ＞０．０５）；慢乙肝疫苗治疗组２年期完全应答率（１５．０％），低于干扰素治疗的对照组（２３．３％）（Ｐ＞０．０５）。结论流行性出血热灭活疫苗作为干扰素诱生剂，可用作慢乙肝病毒携带者，慢乙肝及乙肝肝硬化代偿期患者的转阴治疗，是安全、有效、经济、方便的，值得应用推广。     

慢性乙型肝炎患者血生化指标和血清病毒标志与肝组织病理的相关性研究

目的探讨慢性乙型肝炎（CHB）患者血生化指标和血清病毒标志与肝组织病理的关系。方法对132例CHB患者行肝穿刺活检,进行组织炎症活动度分级（G）和纤维化程度分期（S）,同时检测患者血清总胆红素（TBIL）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、γ-谷氨酰转移酶（y-GT）、总胆汁酸（TBA）、白蛋白（ALB）和血清病毒标记物乙型肝炎病毒e抗原（HBeAg）、乙型肝炎病毒脱氧核糖核酸（HBV—DNA）。结果血清TBIL,ALT、AST、y—GT、TBA平均值随病理分级和分期的增加而逐渐升高,ALB则相反,与肝炎症分级和肝纤维化分期之间有明显相关（P〈0．05）;HBehg的表达与肝炎症分级和肝纤维化分期之间无明显相关（P〉0．05）;HBV—DNA水平与肝炎症变化和纤维化分期无明显相关（P〉0．05）。与病理诊断比较,临床诊断的灵敏度分别为：轻度74．24％（49例）,中度60．38％（32例）,重度53．85％（7例）。结论血清TBIL、ALT、AST、γ—GT、TBA可反映CHB患者肝组织炎症活动的程度;ALB是慢性乙型肝炎病变进展的指标。血清HBeAg的表达和HBV—DNA水平与肝组织病理炎症分级和纤维化分期之间无明显相关性。仅凭血生化指标、血清病毒复制活跃与否判断肝病活动性是不全面的,应将肝组织病理作为判断肝炎活动性和是否抗病毒治疗的主要依据。     

前列腺素E1对慢性重型肝炎患者血清可溶性白细胞介素-6受体及其β链的影响

目的　观察前列腺素E1(PGE1)对慢性重型肝炎患者血清可溶性白细胞介素-6受体(SIL-6R)及其β链(sgp130)的影响。方法　应用酶联免疫吸附法检测16例慢性重型肝炎患者经PGE1治疗前后血清SIL-6R、sgp130的动态变化。结果　慢性重型肝炎患者血清SIL-6R、sgp130水平较健康对照组明显升高(P<0.01),PGE1治疗后血清SIL-6R、sgp130水平较治疗前明显下降(P<0.01),且治疗组死亡率明显下降(P<0.01)。结论　监测血清SIL-6R、sgp130水平能反映慢性重型肝炎的肝损伤程度及判定预后;PGE