Treatment of hepatitis C infection.

There is growing awareness of the health risk posed by hepatitis C virus and fears that an epidemic of 'AIDS proportions' may be just around the corner. As our understanding of the disease increases, it is likely that substantial resources will be spent on developing newer and more effective treatments for hepatitis C infection in the years ahead.     

Mechanisms of hepatitis C virus infection

Hepatitis C virus (HCV) is the major causative agent of chronic non-A, non-B hepatitis. The life cycle of HCV is largely unknown because a reliable culture system has not yet been established. HCV presumably binds to specific receptor(s) and enters cells through endocytosis, as do other members of Flaviviridae. The viral genome is translated into a precursor polyprotein after uncoating, and viral RNA is synthesized by a virus-encoded polymerase complex. Progeny viral particles are released into the luminal side of the endoplasmic reticulum and secreted from the cell after passage through the Golgi apparatus. Understanding the mechanisms of HCV infection is essential to the development of effective new therapies for chronic HCV infection. Several host membrane proteins have been identified as receptor candidates for HCV. Recent advances using pseudotype virus systems have provided information surrounding the initial steps of HCV infection. An HCV RNA replicon system has been useful for elucidating the replication mechanism of HCV. In this review, we summarize our current understanding of the mechanisms of HCV infection and discuss potential antiviral strategies against HCV infection.     

The cytokine profile in patients with chronic type C hepatitis

The purpose of the study was to perform complex evaluation of cytokine status in patients with type C chronic hepatitis (CCH), taking into account its system and local parameters and their correlation with peculiarities of clinical and morphological parameters. The study revealed a significant increase of concentrations of cytokines Th-2, interleukins (IL-4, IL-10), and proinflammatory cytokines (IL -1alpha, IL -12p40, IL -12p70), as well as a significant decrease of Th1-cytokine (IL-2 and interferon-gamma) levels, both in blood and in the supernatant of hepatic tissue samples. The study also found an increase of serum and local tumor necrosis factor (TNF) -alpha and established a correlation between the levels of the system and local cytokines under study, on the one part, and clinical, laboratory and morphological parameters, on the other, which evidences their significant role in CCH immunopathogenesis. The most significant from the clinical point of view are serum and local levels of TNF-alpha, IL-4, IL-12p40; the most important parameters for determination of inflammatory activity of the pathologic process and fibrosis stage are concentrations of IL-4, IL-10, and IL-12p70 in serum and the supernatant of hepatic tissue samples.     

Primary sclerosing cholangitis and hepatitis C virus infection

Two cases of primary sclerosing cholangitis with hepatic C virus infection in a 62-year-old man and a 60-year-old woman are presented. The infection in the man was eradicated with interferon therapy in 1992. Seven years thereafter, endoscopic retrograde cholangiography revealed a diffuse 2.5-cm-long stenotic lesion in the common bile duct which was consequently resected. Histological examination of the resected specimen revealed proliferation of epithelial cells, plasma cell infiltration, and fibrosis in the submucosal layer of the common bile duct. The human leukocyte antigen DR loci were 2 and 9. In the woman, a 6-month course of interferon therapy in 1992 failed to eradicate the infection. Cholangiography in 1999 revealed multiple narrowings and dilatations of intra- and extrahepatic bile ducts. Ultrasound guided biopsy of the liver in 1992 had revealed onionskin lesions around the bile duct epithelium in the portal tract. The human leukocyte antigen DR locus was 2. From these findings, the 2 cases were diagnosed as primary sclerosing cholangitis. Further studies may provide insights into the relation between the pathogenesis of the disease and the infection.     

The epidemiology and control of hepatitis C infection

Hepatitis C is a global public health problem, and a major cause of chronic hepatitis. The virus can cause cirrhosis, liver failure and primary liver cancer. Combination therapy is effective in 50-60 per cent of patients with chronic infection. Prevention initiatives should target high-risk groups, such as injecting drug users.     

不同送检人群HIV、TP和HCV合并感染分析

目的分析人类免疫缺陷病毒(HIV)、梅毒(TP)和丙型肝炎病毒(HCV)合并感染现象在不同送检人群中的表现。方法采用酶联免疫吸附试验和病毒核酸检测192例不同送检人群感染HIV、TP和HCV的情况,分析合并感染的特点。结果 192例送检血液标本均感染HIV,男127例,女65例,其中51例合并感染TP,18例合并感染HCV,7例同时感染以上3种病毒;合并感染者以血液科、传染科、皮肤科、肝病科和戒毒所送检的血液标本为主。结论 HIV与TP和HCV往往呈二重或多重合并感染,加强HIV感染者的健康教育和行为干预意义重大。     

Erythrocyte protoporphyrins in hepatitis C viral infection

OBJECTIVES: Protoporphyrin is the immediate precursor of the heme molecule. Due to a spillover from hemaotopoietic tissue it is regularly found in small amounts in erythrocytes and excreted into the bile. In hereditary erythropoietic protoporphyria excess protoporphyrin accumulates and can cause severe liver damage both by crystallization and induction of oxidative stress. The aim of this investigation was to study protoporphyrin concentrations in other liver disorders. DESIGN AND METHODS: Erythrocyte protoporphyrin and zinc protoporphyrin concentrations were studied in 50 patients with chronic hepatitis C infection and various degrees of liver damage. High-performance liquid chromatographic analysis with fluorescence detection was used. RESULTS: Erythrocyte protoporphyrin was increased in 32% of the patients studied; in 12 patients up to two-fold higher than the maximum of the reference range, in 4 up to three-fold higher (median concentration 98 nmol/L, interquartile range 68-142; maximum 379 nmol/L (reference range: <125 nmol/L)). In 6 of the 10 patients in the subgroup with signs of severe liver dysfunction (decreased serum albumin and prolonged thromboplastin time, elevated serum bilirubin), protoporphyrin was elevated. Erythrocyte zinc protoporphyrin was increased in 7 cases out of all 50 studied; in these seven cases, erythrocyte protoporphyrin was also elevated (median concentration of zinc protoporphyrin in the whole study group: 232 nmol/L, interquartile range 182-342; maximum 827 nmol/L (reference range <464 nmol/L). CONCLUSIONS: Elevated erythrocyte protoporphrin levels are frequently found in patients with advanced chronic hepatitis C infection. Because protoporphyrin is well known to be hepatotoxic, these findings warrant further investigation.     

Treatment of chronic hepatitis C virus infection

OBJECTIVE: To review the literature on the treatment of chronic hepatitis C virus (HCV) infection. DATA SOURCES: MEDLINE search (1986-December 1999) using key words such as HCV, hepatitis, non-A and non-B hepatitis, as well as terms regarding treatment during that time period. DATA SYNTHESIS: HCV infection was initially treated with interferon monotherapy, but only a minority of patients responded to long-term therapy. A higher rate of response in both interferon-na?ve patients and interferon-relapsers has been achieved by using the combination of interferon and ribavarin. Other treatment regimens including high-dose interferon protocols, ursodeoxycholic acid, amantadine, and nonsteroidal antiinflammatory drugs have been less promising. Many alternative therapies are being investigated. CONCLUSIONS: HCV infection is a major public health problem. It is now possible to achieve a cure in nearly 50% of the patients with this infection. Many additional therapies are being evaluated in order to achieve a higher cure rate.     

Thymalfasin for the treatment of chronic hepatitis C infection

Approximately 50% of treatment-naive hepatitis C patients fail to achieve a sustained virologic response with standard peginterferon and ribavirin therapy. Patients who are infected with genotype 1 have high viral loads and are nonresponders to previous therapy, and are even more difficult to treat, underscoring the need for new therapeutic options. Thymalfasin (thymosin-alpha1), in combination with peginterferon-alpha2a, has demonstrated efficacy among difficult-to-treat patients with hepatitis C. The addition of ribavirin to thymalfasin and peginterferon-alpha2a has also exhibited promising results among patients who have genotype 1 hepatitis C, high viral loads and are nonresponders to previous therapy.     

Thymalfasin for the treatment of chronic hepatitis C infection

Approximately 50% of treatment-naive hepatitis C patients fail to achieve a sustained virologic response with standard peginterferon and ribavirin therapy. Patients who are infected with genotype 1 have high viral loads and are nonresponders to previous therapy, and are even more difficult to treat, underscoring the need for new therapeutic options. Thymalfasin (thymosin-α₁), in combination with peginterferon-α_2a, has demonstrated efficacy among difficult-to-treat patients with hepatitis C. The addition of ribavirin to thymalfasin and peginterferon-α_2a has also exhibited promising results among patients who have genotype 1 hepatitis C, high viral loads and are nonresponders to previous therapy.     

Telaprevir for the treatment of chronic hepatitis C infection

Telaprevir is an NS3/4A protease inhibitor that has recently received US FDA approval for the treatment of chronic HCV infection. Telaprevir is given in combination with peg-IFN-α and ribavirin and is indicated for both treatment-naive and treatment-experienced patients with genotype 1 infection. Along with the other first generation NS3/4A protease inhibitor boceprevir, these combination regimens have immediately become the standard of care for genotype 1 patients. The adverse event profile for the combination regimen remains dominated by peg-IFN-α and ribavirin, but there is additional anemia and rash with telaprevir. Owing to telaprevir’s metabolism by the CYP3/4A pathway, drug–drug interactions could lead to toxicity from other medications or decreased efficacy of telaprevir. Viral resistance can develop during treatment with telaprevir, and patients will need to be educated on their role in adherence to minimize the risk of resistance and improve their chances of cure of HCV infection.     

Telaprevir for the treatment of chronic hepatitis C infection

Telaprevir is an NS3/4A protease inhibitor that has recently received US FDA approval for the treatment of chronic HCV infection. Telaprevir is given in combination with peg-IFN-α and ribavirin and is indicated for both treatment-naive and treatment-experienced patients with genotype 1 infection. Along with the other first generation NS3/4A protease inhibitor boceprevir, these combination regimens have immediately become the standard of care for genotype 1 patients. The adverse event profile for the combination regimen remains dominated by peg-IFN-α and ribavirin, but there is additional anemia and rash with telaprevir. Owing to telaprevir's metabolism by the CYP3/4A pathway, drug-drug interactions could lead to toxicity from other medications or decreased efficacy of telaprevir. Viral resistance can develop during treatment with telaprevir, and patients will need to be educated on their role in adherence to minimize the risk of resistance and improve their chances of cure of HCV infection.     

No-fault compensation for transfusion-associated hepatitis B virus, hepatitis C virus, and HIV infection: Italian law and the Tuscan experience

BACKGROUND: On February 25, 1992, in Italy, a law (Number 210; referred to as 210/1992) was promulgated providing economic indemnity for persons infected with hepatitis B virus, hepatitis C virus, and HIV via transfusion or the administration of hemoderivatives. STUDY DESIGN AND METHODS: The requests for compensation presented in the central Italian region of Tuscany from the time of the law's promulgation through December 31, 1996, were analyzed. These requests are surveyed by medical commissions in the regional military hospitals, which must compile a report of the completed assessments, formulate a decision concerning verified illnesses, and express an opinion on the existence of a relationship of causality between the damaging event and the impairment or death of the subjects. RESULTS: Out of 428 requests for indemnity, 372 have been granted and 56 denied. Posttransfusion infections (286 cases) were clearly more prevalent than those due to hemoderivatives (141 cases). Cases of hepatitis, particularly type C, constitute the great majority of the infections for which indemnity was sought, while cases of HIV infection are scarce and in sharp decrease in the data from 1995 and 1996. CONCLUSIONS: Italian Law 210/1992 has been recognized as providing a benefit to persons infected medically, but its efficiency is greatly obstructed by a lack of documentation regarding transfusions performed in the past.