丙型病毒性肝炎感染的临床研究现状

丙型病毒性肝炎,是由丙型肝炎病毒(HCV)引起的传染病,人群普遍有易感性.目前,全球HCV感染者已近1.7亿,且85%的急性HCV感染的病人可发展成慢性丙型肝炎(CHC),CHC的临床表现较轻,但有明显的肝硬化和肝癌发展倾向.从1989年发现HCV至今,对HCV的认识、CHC的诊断及治疗方法的研究有了很大进展.

国际标准化HCV RNA检测推进丙型病毒性肝炎规范化诊疗

丙型病毒性肝炎是较常见的肝脏疾病之一，是导致肝硬化和肝癌的重要原因。中国丙型病毒性肝炎防治现状可以概括为“三高三低”，即“高隐匿、高漏诊、高慢性化、认知率低、就诊率低、治疗率低”。据估计，我国约有1000万丙型病毒性肝炎感染者。2013年国家卫生和计划生育委员会传染病报告丙型病毒性肝炎感染超过20万例，而诊断率仅为2％，接受抗病毒治疗的患者仅为1％。丙型病毒性肝炎给社会带来严重的医疗经济负担。

艾滋病病毒与丙型病毒性肝炎病毒(HIV/HCV)合并感染的临床研究

目的:分析艾滋病病毒与丙型病毒性肝炎病毒(HIV/HCV)合并感染的途径、临床表现、肝脏功能、免疫功能等临床特点。方法:回顾性分析河南中医学院第一附属医院2010年7月至2011年6月HIV/HCV合并感染的住院患者。结果:37例艾滋病住院患者中,22例合并丙型病毒性肝炎(丙肝),占住院患者的59.5%,感染途径以有偿献血为主。合并感染者中15例(68.2%)为慢性肝炎;10例(45.5%)为肝硬化,其中8例已进入失代偿期(36.4%)。合并感染患者CD4+细胞小于200个.μL-1者所占比例与总住院患者中该人群所占比例比较,差异无统计学意义(P<0.05)。结论:HIV/HCV合并感染者常伴有不同程度的肝损伤,其肝脏疾病进展快,肝纤维化肝硬化较多见。HCV对艾滋病病毒本身导致的免疫缺陷影响小,其对艾滋病的影响主要是更容易引起HAART药物的肝毒性。

新形势下医院感染管理模式的探讨

近年来,国内发生了多起医院感染的恶性事件,特别是安徽眼球事件、西安某附属医院新生儿感染暴发事件、山西某医院血透致20名患者的丙型病毒性肝炎感染、严重急性呼吸综合征（severe acute respiratory syndrome,SARS）等,使人们深刻意识到医院感染的严重危害,它已成为重要的公共卫生问题.医院感染控制是医疗安全的重要组成部分,与医院每个部门、每位医务人员息息相关.

Occult persistence and lymphotropism of hepatitis C virus infection

Recent discovery of occult hepatitis C virus (HCV) infection persisting after spontaneous or antiviral therapy-induced resolution of hepatitis C was made possible by the introduction of nucleic acid amplification assays capable of detecting HCV RNA at sensitivities superseding those offered by clinical tests. Although individuals with this seemingly silent HCV infection are usually anti-HCV antibody reactive and have normal liver function tests, occult HCV infection has also been reported in anti-HCV-negative individuals with persistently elevated liver enzymes of unknown etiology. Studies have shown that HCV RNA can persist for years in serum, lymphomononuclear cells and liver in the absence of clinical symptoms, although histological evidence of a mild inflammatory liver injury can be occasionally encountered. Furthermore, while HCV RNA can be detected in circulating lymphoid cells in approximately 30% of cases, a short-term culture under stimulatory conditions augments HCV replication in these cells allowing detection of virus in otherwise HCV-negative cases. HCV infects different immune cell subsets, including CD4+ and CD8+ T lymphocytes, B cells and monocytes. Studies employing clonal sequencing and single-stranded conformational polymorphism analyses have revealed unique HCV variants residing in immune cells, further strengthening the notion of HCV lymphotropism. Overall, the data accumulated suggest that occult HCV infection is a common consequence of resolution of symptomatic hepatitis C and that examination of the cells of the immune system is an effective approach to diagnosis of HCV infection and its long-term persistence. Further work is required to fully realize pathogenic and epidemiological consequences of occult HCV persistence.

Mechanisms and significance of liver steatosis in hepatitis C virus infection

The pathogenesis of liver damage associated with chronic hepatitis C virus （HCV） infection is thought to be largely immunomediated. However, some frequent histoo pathological features, such as steatosis, suggest a direct cytopathic effect of HCV. The direct responsibility of HCV in the pathogenesis of steatosis is shown by： （1） the association with HCV genotype 3 infection, suggesting that some viral sequences are involved in the intracellular aco cumulation of lipids; （2） the correlation between severity of steatosis and HCV replication levels; （3） association between response to treatment and disappearance of steatosis. Experimental studies have shown that the nuo cleocapsid protein of HCV （core protein） is capable and sufficient to induce lipid accumulation in hepatocytes. Moreover, the observation that chronic hepatitis C pao tients have reduced serum levels of ApoB suggests an interference with the very-low density lipoprotein （VLDL） assembly, although other mechanisms are possible. In patients with sustained virological response induced by antiviral therapy, such levels are normalized. Other obo servations suggest that the pathogenesis of steatosis in chronic hepatitis C is not solely due to HCV. The origin of the mild steatosis observed in most patients may be metabolic, since its severity correlates with body mass index and insulin resistance. Most studies have shown a correlation between presence and/or severity of steatosis and fibrosis stage, but it is unclear whether this effect is direct or mediated by the associated insulin resistance, increased susceptibility to apoptosis, or by inflammao tory cytokines. Finally, steatosis negatively influences the rate of response to antiviral treatment, as confirmed by large clinical trials. Management of steatosis in chronic hepatitis C requires knowledge of its pathogenesis and may involve both life-style changes and pharmacological interventions, although the latter remain largely experio mental.

Prevalence and risk factors of asymptomatic hepatitis C virus infection in Egyptian children

AIM: To identify the prevalence, risk factors and manifestations of asymptomatic hepatitis C virus (HCV) infection in Egyptian children. METHODS: Children at the age of 1-9 years were screened for HCV antibodies and alanine aminotransferase (ALT) levels. Every child with elevated ALT and/or detectable HCV antibodies was tested for HCV RNA by RT-PCR and compared with two negative controls for risk factors and signs and symptoms of liver disease.RESULTS: We screened 1042 children, six of them had elevated ALT, negative HCV antibody and positive RNA, likely representing acute hepatitis C cases. Fifteen children were HCV seropositive, 5 of them were HCV RNA positive. Asymptomatic HCV infection was present in 2.02% (positive results for either HCV antibodies or HCV-RNA or both). Symptoms such as diarrhea, abdominal pain, history of fatigue and school absence because of illness and risk factors such as dental care were significantly more common among HCV positive cases than among controls. None of the HCV positive children was diagnosed as having signs of advanced liver disease upon clinical or ultrasonographic examination. CONCLUSION: Asymptomatic HCV infection is detectable in 2.02% Egyptian children.

Polymorphisms of some cytokines and chronic hepatitis B and C virus infection

AIM： To study the relationship between the polymorphisms in some cytokines and the outcome of hepatitis B virus （HBV） and hepatitis C virus （HCV） infection. METHODS： Samples were obtained from 203 patients infected with HBV and/or HCV while donating plasma in 1987, and 74 controls were obtained from a rural area of North China. Antibodies to HBV or HCV antigens were detected by enzyme-linked imrnunoassay. The presence of viral particles in the serum was determined by nested reverse-transcriptase polymerase chain reaction （PCR）. Hepatocellular injury, as revealed by alanine aminotransferase （ALT） and aspartate aminotransferase level, was detected by a Beckman LX-20 analyzer. DNA was extracted from blood cells. Then, the single nucleotide polymorphisms of IL-2-330, IFN-γ＋874, IL-10-1082/-592 and IL-4-589 were investigated by restriction fragment length polymorphism-PCR or sequence specific primer-PCR.RESULTS： Persistent infection with HBV, HCV, and HBV/HCV coinfection was associated with IL-2-330 TT genotype and T allele, IFN-γ＋874 AA genotype, and IL-10-1082 AA genotype. The clinical outcome of HBV and/or HCV infection was associated with IL-2-330 TT genotype and T allele, IFN-γ＋874 AA genotype, and IL-10-1082 AA genotype. IL-2-330 GG genotype frequency showed a negative correlation with clinical progression, IL-10-1082 AA genotype frequency showed a positive correlation and IL-10-1082 AG genotype frequency showed a negative correlation with clinical progression. HCV RNA positive expression was associated with IL-10-1082 AA genotype and the A allele frequency. Abnormal serum ALT level was associated with IL-10-592 AC genotype frequency and IL-4-589 CC genotype, CT genotype, and the C allele. CONCLUSION： These results suggest that polymorphisms in some cytokine genes influence persistent HBV and HCV infection, clinical outcome, HCV replication, and liver damage.

A comparative review of HLA associations with hepatitis Band C viral infections across global populations

Hepatitis B （HBV） and hepatitis C （HCV） viral infection or co-infection leads to risk of development of chronic infection, cirrhosis and hepatocellular carcinoma （HCC）. Immigration and globalization have added to the challenges of public health concerns regarding chronic HBV and HCV infections worldwide. The aim of this study is to review existing global literature across ethnic populations on HBV and HCV related human leukocyte antigen （HLA） associations in relation to susceptibility, viral persistence and treatment. Extensive literature search was conducted to explore the HLA associations in HBV and HCV infections reported across global populations over the past decade to understand the knowledge status, weaknesses and strengths of this information in different ethnic populations. HLA DR13 is consistently associated with HBV clearance globally. HLADRB1＊11/＊12 alleles and DQB1＊0301 are associated with HBV persistence but with HCV clearance worldwide. Consistent association of DRB1＊03 and ＊07 is observed with HCV susceptibility and non-responsiveness to HBV vaccination across the population. HLA DR13 is protective for vertical HBV and HCV transmission in Chinese and Italian neonates, but different alleles are associated with their susceptibility in these populations. HLA class I molecule interactions with Killer cell immunoglobulin like receptors （KIR） of natural killer （NK） cells modulate HCV infection outcome via regulating immune regulatory cells and molecules. HLA associations with HBV vaccination, interferon therapy in HBV and HCV, and with extra hepatic manifestations of viral hepatitis are also discussed. Systematic studies in compliance with global regulatory standards are required to identify the HLA specific viral epitope, stage specific T cell populations interacting with different HLA alleles during disease progression and viral clearance of chronic HBV or HCV infections among different ethnic populations. These studies would facilitate stage specific therapeutic strategies for clearance of HBV and HCV infections or co-infections across global populations and aid in identification of HBV-HCV combined vaccine. HLA associations of chronic HBV or HCV development with confounding host factors including alcohol, drug abuse, insulin resistance, age and gender are lacking and warrant detailed investigation across global populations.

Fibrosing cholestatic hepatitis following cytotoxic chemotherapy for small-cell lung cancer

Fibrosing cholestatic hepatitis(FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver,renal or bone transplantation recipients and in leukemia and lymphoma patients after conventional cytotoxic chemotherapy.FCH constitutes a well-described form of fulminant hepatitis having extensive fibrosis and severe cholestasis as its most characteristic pathological findings.Here,we report a case of a 49-year-old patient diagnosed with small-cell lung cancer who developed this condition following conventional chemotherapy-induced immunosuppression.This is the first reported case in the literature of FCH after conventional chemotherapy for a solid tumor.In addition to a detailed report of the case,a physiopathological examination of this potentially life-threatening condition and its treatment options are discussed.

Current treatment options and response rates in children with chronic hepatitis C

Vertical transmission has become the most common mode of transmission of hepatitis C virus (HCV) in children.The rate of perinatal transmission from an HCVinfected mother to her child ranges from 2% to 5% and the prevalence of HCV in children in developed countries ranges between 0.1% and 0.4%.Spontaneous viral clearance seems to be dependent on the genotype and has been reported between 2.4%-25%.For chronically infected patients,treatment with recombinant polyethylene glycol (PEG)-interferon α-2b and daily ribavirin has now been approved as standard treatment for children 2-17 years of age.In five large prospective studies,a total of 318 children and adolescents aged 3-17 years were treated either with subcutaneous PEG-interferon α-2b at a dose of 1-1.5 μg/kg or 60 μg/m2 once a week in combination with oral ribavirin (15 mg/kg per day) or PEG-interferon α-2a with ribavirin.Subjects with genotype 1 and 4 received the medication for 48 wk and individuals with genotype 2 and 3 mainly for 24 wk.Overall sustained viral response (SVR) was achieved in 193/318 (60.7%) of treated patients.Stratified for genotype;120/234 (51%) with genotype 1,68/73 (93%) with genotype 2/3,and 6/11 (55%) with genotype 4 showed SVR.Relapse rate was between 7.7% and 17%.Overall,treatment was well tolerated;how-ever,notable side effects were present in approximately 20%.According to recent experiences in the treatment of chronic hepatitis C in children and adolescents,a combination of PEG-interferon α with ribavirin has been found to be well tolerated and highly efficacious,particularly in individuals with genotype 2/3.Thus,this treatment can be recommended as standard of care until more effective treatment options will become available for genotype 1 patients.

Construction of a chimeric hepatitis C virus replicon based on a strain isolated from a chronic hepatitis C patient

Subgenomic replicons of hepatitis C virus （HCV） have been widely used for studying HCV replication.Here,we report a new subgenomic replicon based on a strain isolated from a chronically infected patient.The coding sequence of HCV was recovered from a Chinese chronic hepatitis C patient displaying high serum HCV copy numbers.A consensus sequence designated as CCH strain was constructed based on the sequences of five clones and this was classified by sequence alignment as belonging to genotype 2a.The subgenomic replicon of CCH was replication-deficient in cell culture,due to dysfunctions in NS3 and NS5B.Various JFH1/CCH chimeric replicons were constructed,and specific mutations were introduced.The introduction of mutations could partially restore the replication of chimeric replicons.A replication-competent chimeric construct was finally obtained by the introduction of NS3 from JFH1 into the backbone of the CCH strain.

Treatment of genotype 2 and 3 chronic hepatitis C virus-infected patients

AIM： Before pegylated interferon alpha （IFN） was introduced for the therapy of chronic hepatitis C virus （HCV）-induced hepatitis, conventional thrice weekly IFN therapy was supplemented by ribavirin. Also, at that time, higher and more frequent doses of IFN were expected to be more effective than the standard regimen of 3 MU thrice weekly. As ribavirin significantly increases side effects and negatively influences the quality of life particularly in young patients, we started a prospective non-randomized study with a daily IFN-2a monotherapy as an initial treatment for chronic hepatitis C. METHODS： Forty-six consecutive chronic HCV-infected patients received 3 MU IFN-2a per day as an initial treatment. Patients with genotype 2 or 3 （n = 12） were treated for 24 wk, and patients with genotypes other than 2 or 3 （n = 34） for 48 wk. Treatment outcome was followed up for 48 wk after the end of treatment （EOT）. Virological response was defined as the absence of detectable serum HCV-RNA. Patients without virological response at 12 wk after the start of treatment received low-dose ribavirin （10 mg（kg·d）） additionally. RESULTS： During treatment, three genotype 3 patients were excluded from the study due to incompliance. The remaining patients （n = 9） infected with genotype 2 or 3 showed an initial virological response rate of 100%. Six patients （66.7%） were still found to be virus-free at the end of follow-up period. In these patients, initial virological response was evident already after 2 wk of treatment. In contrast, initial virological response occurred first after 4 wk of treatment in the three patients who relapsed （33.3%）. In comparison, patients infected with genotypes other than 2 or 3 （n = 34） showed an initial virological response rate of only 23.5% （n = 8）, and even in combination with ribavirin a sustained virological response （SVR） rate of only 11.8% （n = 4） could be achieved. CONCLUSION： In chronic HCV-infected patients with genotype 2 or 3, a SVR can be expected after 24 wk of daily dose IFN-2a treatment without ribavirin, if initial virological response develops early. This finding is worth to be confirmed in a prospective randomized study with pegylated IFN.

Optimal control analysis of hepatitis C virus with acute and chronic stages in the presence of treatment and infected immigrants

In this paper, we consider a deterministic hepatitis C virus （HCV） model and study the impact of optimal control on the screening of immigrants and treatment of HCV on the transmission dynamics of the disease in a homogeneous population with constant immigration of susceptibles. First, we derived the condition in which disease-free equilibrium is locally asymptotically stable and established that a stable disease-free equilibrium can only be achieved in the absence of infective immigrants. Second we investigated the impact of each control mechanism individually and the combinations of these strategies in the control of HCV. The costs associated with each of these strategies are also investigated by formulating the costs function problem as an optimal control problem, and we then use the Pontryagin＇s Maximum Principle to solve the optimal control problems. From the numerical simulations we found that the optimal combination of treatment of acute-infected and chronic-infected individuals control strategy produced the same results as the combination of the three strategies （combination of screening of immigrants, treatment of acute-infected and chronic-infected individuals）. By our model and these results, we suggest the treatment of acute-infected and chronic-infected individuals control strategy should be optimized where resources are scarce, because the implementation of the three strategies （combination of screening of immigrants, treatment of acute-infected and chronic-infected individuals） would imply additional cost.

Dynamical analysis of a class of hepatitis C virus infection models with application of optimal control

In this paper, we deal with the problem of optimal control of a deterministic model of hepatitis C virus （HCV）. In the first part of our analysis, a mathematical modeling of HCV dynamics which can be controlled by antiretroviral therapy as fixed controls has been presented and analyzed which incorporates two mechanisms： infection by free virions and the direct cell-to-cell transmission. Basic reproduction number is calculated and the existence and stability of equilibria are investigated. In the second part, the optimal control problem representing drug treatment strategies of the model is explored considering control parameters as time-dependent in order to minimize not only the population of infected cells but also the associated costs. At the end of the paper, the impact of combination of the strategies in the control of HCV and their effectiveness are compared by numerical simulation.