免疫疗法联合干扰素治疗慢性乙型肝炎的初步研究

探讨免疫疗法联合干扰素治疗不同免疫应答期慢性HBV感染患者的疗效.145例慢性乙型肝炎患者(免疫耐受期66例,免疫清除期64例,残余整合期15例)随机分为联合治疗组(乙肝疫苗 胸腺肽 绿脓杆菌菌毛 干扰素,其中免疫耐受期42例,免疫清除期46例.共88例)和对照组(单用干扰素治疗,其中免疫耐受期24例,免疫清除期18例.共42例),观察ALT及病毒标志物变化.治疗后,免疫清除期联合治疗组的ALT复常率、HBeAg、HBV DNA阴转率和HBeAg/抗-HBe血清转换率均显著高于对照组(P＜0.05).免疫耐受期,治疗组HBeAg、HBV DNA阴转率和HBeAg/抗-HBe转换率均明显高于对照组(P＜0.05).免疫疗法联合干扰素治疗慢性乙型肝炎,疗效明显优于单用干扰素治疗.     

Occult hepatitis C virus infection among haemodialysis patients

Background and study aims

Hepatitis C virus (HCV) infection is a severe problem among patients on maintenance haemodialysis who are at particular risk for blood-borne infections because of prolonged vascular access and potential for exposure to contaminated equipment. Occult hepatitis C virus infection (OCI) is defined as the presence of HCV RNA in liver or peripheral blood mononuclear cells (PBMCs) in the absence of detectable HCV antibody or HCV RNA in the serum. In this study, we aimed to investigate the existence of occult hepatitis C virus infection in PBMCs of haemodialysis (HD) patients in one center. Moreover, we tried to link the condition to risk factors associated with HCV infection in those patients.

Treatment of chronic hepatitis C virus infection in patients with cirrhosis

Chronic hepatitis C virus (HCV) infection eventually leads to cirrhosis in 20–30% of patients and to hepatocellular carcinoma (HCC) in 1–5% of patients. Rates of sustained virological response with standard interferon-α (IFN-α) are low in patients without cirrhosis (generally < 20%) and are even lower in those with cirrhosis. Combination therapy with IFN and ribavirin improves response rates in patients with chronic hepatitis C without cirrhosis, and the results from subgroups of HCV-infected patients with advanced fibrosis or cirrhosis are encouraging. Importantly, treatment with IFN slows progression of liver fibrosis, regardless of HCV genotype or early response to therapy, and reduces the risk of HCC by two- to fivefold. The risk of development of HCC is also lower in patients who show at least a partial response to IFN therapy compared with those who show no response. There is a clear need for more definitive studies of treatment in patients with chronic hepatitis C and cirrhosis, ideally using therapies with greater efficacy. Nonetheless, based on the potential to slow the progression of liver fibrosis (regardless of treatment response) and to reduce the risk of HCC, a greater number of HCV-infected patients with cirrhosis should be considered as candidates for IFN treatment. Preliminary data indicate that pegylated IFNs have improved virological response rates and may have additional clinical benefits in the prevention or reduction of fibrosis and retardation of progression of cirrhosis and HCC in these patients.     

Steatosis and bile duct damage in chronic hepatitis C: distribution and relationships in a group of Northern Italian patients

Abstract: Background/Aims: Hepatitis C virus (HCV) related disease follows a long, benign course and most affected patients have mild disease. Liver biopsy is mandatory to grade and stage the disease. Characteristic, though non-specific, HCV histological lesions such as bile duct damage and steatosis have been singled out but their association with non-histological parameters has not been completely defined. Our aim was to study the relationships among these histological lesions and clinical, biochemical, functional and virological characteristics in a group of Northern Italian patients with chronic hepatitis. Methods: We studied 172 patients with HCV-related chronic hepatitis. Patients were divided into groups on the basis of histology including bile duct damage and steatosis. Clinical, biochemical, functional and virological profiles were related to histological findings. Results: Histological grading and staging of disease increased as the age of patients increased. Steatosis was present in 70% of our patients and was related to a higher degree of fibrosis and to decreased functional activity. The prevalence of bile duct damage was 20%. This lesion was present in older patients with higher staging and impaired liver function. Biochemically it was associated with an increase in aspartate aminotransferase, gammaglutamyltranspeptidase, alkaline phosphatase, and total bilirubin. Conclusions: In the population we studied, HCV chronic hepatitis was predominantly a mild disease. Moreover both steatosis and bile duct damage were also mild. Steatosis was associated with fibrosis and this might influence liver metabolic function. Bile duct lesions were found in older patients with advanced disease showing biochemical evidence of cholestasis. The molecular role HCV might play in the pathogenesis of these histological features should be addressed in further studies.     

Hepatitis C infection among Dutch haemophilia patients: a nationwide cross-sectional study of prevalence and antiviral treatment

Hepatitis C is a major co-morbidity among patients with haemophilia who received inadequately or non-virus-inactivated clotting factor concentrates before 1992. The objectives of this study were to investigate the prevalence of hepatitis C and the use of antiviral therapies during the last decade among patients with haemophilia in the Netherlands. We performed a cross-sectional study and a questionnaire was sent to all 1519 patients known with haemophilia in the Netherlands between 2001 and 2002. The study population for the present study consisted of 771 patients who had received clotting factor products before 1992 of whom 638 reported their hepatitis C status. In total, 441 of the 638 (68%) patients ever had a positive test for hepatitis C virus (HCV); 344 patients (54%) had a current infection, and 97 (15%) had cleared the virus. Among 344 patients currently HCV infected, 111 (32%) had received treatment for hepatitis C, while 34% (33/97) of patients with an infection in the past had been treated for hepatitis C. In 2002 the prevalence of hepatitis C among patients with haemophilia who received clotting factor products before 1992 was 54%. The majority of patients with a current HCV infection had not been treated with antiviral therapy.     

Efficacy of lamivudine re-treatment for relapsed patients after an initial lamivudine therapy in HBeAg-positive chronic hepatitis B

The efficacy of lamivudine re-treatment in chronic hepatitis B (CHB) patients who relapse after HBeAg seroconversion with lamivudine has not been investigated. The aim of this study was to evaluate the efficacy of lamivudine re-treatment in relapsed patients. Among 192 patients who had achieved HBeAg seroconversion with lamivudine at a dose of 100 mg/day, 121 patients discontinued lamivudine. Relapse occurred in 49 patients (40.5%). Thirty-three relapsed patients received lamivudine re-treatment for at least 6 months. The mean duration of lamivudine re-treatment was 16 months and the follow-up period was 8.9 months. HBeAg seroconversion was achieved in 23 patients (69.7%). The cumulative HBeAg seroconversion rates at 5, 9, and 12 months were 60, 64, and 67%, respectively. The mean time to HBeAg seroconversion in lamivudine re-treatment was shorter than that in the initial therapy (4.7 months vs. 9.7 months). Viral breakthrough occurred in six (18.2%) patients. All patients with viral breakthrough were accompanied by elevation of serum alanine aminotransferase (ALT) levels. Among 15 patients who discontinued lamivudine re-treatment after HBeAg seroconversion, relapse occurred in six patients (40%). All relapses occurred within 9 months after the discontinuation of lamivudine re-treatment. In conclusion, lamivudine re-treatment in relapsed patients after initial lamivudine therapy had a higher response rate and shorter duration to HBeAg seroconversion than during the initial therapy. However, HBeAg seroconversion induced by lamivudine re-treatment was not durable.     

Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes

BACKGROUND & AIMS: Studies on the early steps in the life cycle of hepatitis B virus have been hampered by the lack of readily available target cells. In this study, we mapped a defined virus attachment site to primary hepatocytes that is essential for infection. METHODS: We used purified virus particles from human carrier plasma as an inoculum and primary cultures of tupaia hepatocytes as susceptible target cells and studied the inhibitory effect of amino-terminally acylated preS1-derived lipopeptides on infection interference. RESULTS: Infectivity of virus could be blocked efficiently in this system by amino-terminally acylated peptides containing amino acids 2-18 from the preS1 domain. The addition of amino acids 28-48 enhanced the inhibitory capacity, whereas amino acids 49-78 did not contribute to inhibition. Myristoylated preS1 peptides 2-48 bound strongly to tupaia hepatocytes but not to nonhepatic cells or rodent hepatocytes and thereby inhibited infection even at concentrations of 1 nmol/L completely. Particles consisting only of the small hepatitis B surface protein-the active component of current hepatitis B vaccines-did not bind at all to tupaia hepatocytes, but the addition of the preS1 domain to the particles allowed binding. CONCLUSIONS: The preS1 sequence 2-48 mediates attachment of the virus to its target cells, whereas the small surface protein seems to be involved in other steps. These findings indicate that the current subunit hepatitis B vaccines may be improved by the addition of distinct preS1 epitopes. Moreover, preS1 lipopeptides are promising candidates for specific antiviral therapy against hepatitis B infections.     

Ethnic and cultural determinants influence risk assessment for hepatitis C acquisition

BACKGROUND AND AIM: In the developed world hepatitis C virus (HCV) infection is predominantly associated with sharing contaminated equipment between injecting drug users (IDU). In developing countries inadequately sterilized medical equipment, transmission of infected blood and cultural practices have been implicated. Accurate risk factor assessment is essential for education targeted at risk reduction in culturally diverse populations. METHODS: Ninety Australian-born Caucasians and 72 South-east Asian (SEA) HCV patients attending a Melbourne hospital liver clinic completed a questionnaire which assessed risk factor profile, perceived risk factors, knowledge of risk factors and methods to minimize transmission. Medical records were audited to identify doctor assessment of risk factors. RESULTS: Risk factors in Caucasians were IDU, body piercing and tattooing (89%, 47% and 32%, respectively). Risk factors in SEA patients were injection therapy, dental therapy and surgery (89%, 70% and 38%, respectively). Most Caucasian patients (94%) correctly identified their mode of acquisition compared with 33% of SEA patients (P < 0.0001). Accurate risk factor documentation in medical records was more common in Caucasians (96 vs 32%; P < 0.0001). The majority of patients identified blood-to-blood and sexual/vertical transmission as important modes of acquisition. However, 33% of SEA patients believed transmission occurred through food, water and poor hygiene and 80% did not identify therapeutic injection or traditional medical practices as risk factors. Education provided to SEA patients did not address less well established routes of transmission. CONCLUSIONS: Ethnicity influences perception and knowledge of risk factors. Improved assessment of risk factors in high-risk ethnic groups is needed. Education should be culturally appropriate and address the concerns of all populations with HCV.     

Nucleos(t)ide analogues for hepatitis B virus: Strategies for long-term success

Nucleoside and nucleotide analogues are potent HBV suppressors, but these agents rarely eradicate HBV. Therefore, the durability of viral response is a problem, and long-term therapy is usually required to ensure maintained HBV suppression. Studies have shown that long-term therapy starting with lamivudine may significantly improve survival, reduce the risk of liver-related major complications, and prevent the development of cirrhosis and HCC in chronic hepatitis B patients. However, drug resistance is a critical challenge during long-term nucleos(t)ide analogue maintenance therapy. The emergence of these mutants is characterized by an increasing level of serum HBV DNA, elevation of ALT level, and even hepatitis flare or decompensation. The prevention and proper management of drug resistance are crucial to ensure long-term success. To start treatment in the right patients at the right time with the right drug is essential in minimizing the problem of drug resistance. Each of these agents has a different profile of resistant mutations. In choosing a direct antiviral agent to initiate therapy, resistance profile is a crucial factor to consider, apart from potency and cost. In the case of drug resistance emerging, timely institution of a drug without cross-resistance may rescue the adverse effects of drug resistance and ensure the long-term success of nucleos(t)ide analogue therapy. To develop strategies for enhancing the therapeutic response and shortening the duration of therapy is an ultimate goal to avoid the problems of drug resistance.⁶⁸

• nucleos(t)ide analogues for hepatitis B virus (HBV) are highly effective in suppressing HBV replication but rarely eliminate the virus

• long-term therapy is usually required

• emergence of drug-resistant HBV mutations is a critical challenge

• to treat the right patient at the right time with the drug with highest genetic barrier to drug resistance is essential to minimize the problem with drug resistance

• the strategy of on-treatment adjustment based on level of suppression of HBV DNA needs to be clarified

• studies are needed to find the optimal combination therapy for both better therapeutic efficacy and less drug resistance

• oral antiviral agents able to attack cccDNA are urgently needed