Nanomedicines in the treatment of patients with hepatitis C co-infected with HIV--focus on pegylated interferon-alpha

In immuno-competent individuals, the natural course of chronic hepatitis C virus (HCV) infection is highly variable and 5%-30% of patients develop cirrhosis over 20 years. Co-infection with HCV and human immunodeficiency virus (HIV) is an important prognostic factor and associated with more frequent and accelerated progression to cirrhosis. Until recently HIV/AIDS-related complications were life limiting in patients co-infected with HCV; the introduction of highly active antiretroviral treatment (HAART) and the better prognosis of HIV infection has made HCV-related complications an emerging health problem in HCV/HIV coinfected individuals. Treatment of chronic HCV infection has also evolved since the introduction of interferon-alpha. Recently, introduction of pegylated interferon-alpha (peginterferon-alpha) has resulted in an increase in sustained virus clearance rates of up to 80% in selected genotypes and patient populations. The safety and efficacy of modern anti HCV treatment regimens - based on peginterferon-alpha in combination with ribavirin - was evaluated in 4 controlled trials. Sustained clearance of hepatitis C virus can be achieved in up to 35% of patients with HIV/HCV co-infection, and novel HCV treatment regimens based on peginterferon-alpha have no negative effect on the control of HIV disease. In conclusion, if HIV infection is well controlled and CD4+ cell counts >100/mm3, treatment of chronic hepatitis C with peginterferon in combination with ribavirin is safe and should be given for 48 weeks regardless of the HCV genotype. Introduction of peginterferon-alpha has significantly improved adherence to treatment and treatment efficacy; in particular sustained virologic response in patients with HCV genotype 1 or 4 infection improved, but sustained viral clearance in only 7%-38% of patients infected with genotype I and 4 cannot be the final step in development of effective treatments in patients with HCV/HIV co-infection.     

Interferon signaling in the liver during hepatitis C virus infection

Hepatitis C virus is a global health concern, estimated to infect 2-3% of the world's population. Inter-individual differences in the course of infection and response to therapy, highlighted by recent genomewide association studies, point to the crucial role of the host immune system in the efficient control of infection. Ongoing progress in the studies of the role of innate immunity during hepatitis C virus infection has improved our understanding of the intricacies of the host-virus interactions. In this review, we summarize and discuss the current knowledge concerning interferon signaling in the liver during acute and chronic hepatitis C virus infection and its implications for the outcome of interferon-α-based antiviral therapies.     

Detection of SEN virus in the general population and different risk groups in Slovakia

Sera of 426 adult persons were examined to assess the prevalence of SEN virus (SENV) infection in Slovakia and to determine the importance of different risk factors for parenteral transmission. SENV prevalence was determined by the PCR method using primers of SENV-D and SENV-H strains. Positive results were found in 10 of 37 patients with acute hepatitis of unknown etiology, 7 of 38 with acute hepatitis B, 17 of 44 with chronic hepatitis B, 29 of 102 with chronic hepatitis C, 36 of 72 hemodialysis patients, 2 of 33 health care workers and 24 of 100 persons from the control group. The highest prevalence of SENV was among hemodialysis patients, significantly higher than in the groups of health care workers, acute hepatitis B and controls. The lowest prevalence was in health care workers group, significantly lower also in comparison with groups of chronic hepatitis B and C. Among the possible risk factors of virus transmission the average duration of hemodialysis (1.15 vs. 0.50 years), number of surgeries (1.60 vs. 1.10) and transfusions (1.34 vs. 0.94) showed notable differences in terms of SENV infection. Bilirubin and aminotransferase levels did not differ between SENV-positive and -negative groups. No pathogenetic role of SEN virus in liver injury was confirmed.     

A structural protein of hepatitis C virus expressed in E. coli facilitates accurate detection of hepatitis C virus.

A putative core protein derived from hepatitis C virus was expressed in E. coli. More than 5% of the total protein expressed in the bacteria after induction by isopropylthio-beta-D-galactoside was shown to be the expected protein. Western blotting with this E. coli lysate proved to be more efficient than ELISA with a non-structural viral protein, C100, to detect infection of hepatitis C virus in the sera of patients with non-A, non-B chronic hepatitis, hepatocellular carcinoma as well as in sera from healthy persons.     

树鼩肝炎动物模型的研究进展

肝炎的的大范围流行已成为国内外关注的重要公共卫生问题之一。甲肝、乙肝虽已有疫苗,但不能忽视未来由于病毒变异所带来的威胁。丙肝目前尚未发现非常有效的疫苗,且丙肝的病理学机制也尚未完全清晰,主要原因是缺乏理想的动物模型。树胸属于低等灵长类动物。研究发现,他对很多人类疾病易感,所以建立肝炎树胸动物模型成为现在肝炎研究的一个热点。本文介绍了各型肝炎主要是甲、乙、丙型肝炎研究中建立树胸动物模型的自内外进展情况及存在的问题。     

Synergy of small molecular inhibitors of hepatitis C virus replication directed at multiple viral targets

Chronic hepatitis C virus (HCV) infection is a significant worldwide health problem with limited therapeutic options. A number of novel, small molecular inhibitors of HCV replication are now entering early clinical trials in humans. Resistance to small molecular inhibitors is likely to be a significant hurdle to their use in patients. A systematic assessment of combinations of interferon and/or novel anti-hepatitis C virus agents from several different mechanistic classes was performed in vitro. Combinations of inhibitors with different mechanisms of action consistently demonstrated more synergy than did compounds with similar mechanisms of action. These results suggest that combinations of inhibitors with different mechanisms of action should be prioritized for assessment in clinical trials for chronic hepatitis C virus infection.     

Integration of hepatitis B vaccination into national immunisation programmes. Viral Hepatitis Prevention Board.

Hepatitis B is a major public health problem even though safe and effective vaccines have been available for over 10 years. Because hepatitis B infection is largely asymptomatic with long term complications occurring after many years it has not received the attention it deserves. Strategies to immunise those at high risk have failed to control the disease. Delegates to the World Health Assembly of the World Health Organisation recommended in May 1992 that all countries should integrate hepatitis B vaccination into their national immunisation programmes by 1997. Some western European countries remain unconvinced that the burden of disease warrants the expense of universal vaccination. However, epidemiological data and economic evaluation show that universal hepatitis B vaccination is cost effective in countries with low endemicity and that it will control hepatitis B, reinforcing the necessity for action.     

Effect of concurrent acute infection with hepatitis C virus on acute hepatitis B virus infection.

OBJECTIVE--To investigate the possible interference with acute hepatitis B virus infection by co-infection with hepatitis C virus. DESIGN--Analysis of stored sera collected for transfusion transmitted viruses study in 1970s. SETTING--Four major medical centres in the United States. PATIENTS--12 recipients of blood infected with hepatitis B virus. MAIN OUTCOME MEASURES--In 1970s, presence of antibodies in hepatitis B virus and raised serum alanine aminotransferase concentration; detection of antibodies to hepatitis C virus with new enzyme linked immunoassays. RESULTS--Five of the 12 patients were coinfected with hepatitis C virus. Hepatitis B surface antigen was first detected at day 59 in patients infected with hepatitis B virus alone and at day 97 in those coinfected with hepatitis C virus (p = 0.01); median durations of antigenaemia were 83 and 21 days respectively (p = 0.05), and the antigen concentration was lower in the coinfected patients. Alanine aminotransferase patterns were uniphasic when hepatitis B virus infection occurred alone (range 479-2465 IU/l) and biphasic in patients with combined acute infection (no value > 380 IU/l; p = 0.0025). Four coinfected recipients developed chronic hepatitis C virus infection. The fifth patient was followed for only four months. CONCLUSIONS--Acute coinfection with hepatitis C virus and hepatitis B virus inhibits hepatitis B virus infection in humans, and onset of hepatitis B may reduce the severity of hepatitis C virus infection but not frequency of chronicity. Alanine aminotransferase concentration showed a biphasic pattern in dual infection.     

丙型肝炎病毒感染与肝细胞癌相关关系的研究进展

世界上有数亿的人口患有丙型肝炎,而丙型肝炎病毒（HCV）的感染易转为慢性,引起肝细胞炎性坏死及再生,导致肝纤维化、硬化甚至肝细胞癌（HCC）,是危害人类健康的一个重要卫生问题。HCV的感染可导致HCC的发生,但HCV相关性HCC的发生机制尚不清楚。免疫逃避机制是感染慢性化的一个重要原因,病毒通过其基因组编码的蛋白使肝细胞发生转化,可能是肝细胞癌变的重要机制。     

Assessment of peripheral DNA damage by alkaline comet assay in maintenance hemodialysis subjects with hepatitis C infection

Despite the high prevalence of hepatitis C infection among hemodialysis subjects, there is no information concerning the DNA damage of hepatitis C (+) hemodialysis subjects. We aimed to find out if there is any additional effect of hepatitis C infection on peripheral DNA damage in maintenance hemodialysis subjects. Fifteen hepatitis C (+) and 22 hepatitis C (-) hemodialysis subjects, 21 hepatitis C subjects without renal disease, and 22 healthy controls were enrolled. Peripheral DNA damage was assayed using alkaline comet assay. Median DNA damage levels of the study groups were as follows: hepatitis C (+) maintenance hemodialysis subjects, 88 (0-232); hepatitis C (-) maintenance hemodialysis subjects, 58 (0-228); hepatitis C (+) subjects without renal disease, 112 (44-252); controls, 26 (0-72). DNA damage level was significantly higher among hepatitis C (+) subjects without renal disease than hepatitis C (-) maintenance hemodialysis subjects and healthy controls (both p<0.05/6). Both maintenance hemodialysis subjects with and without HCV infection had significantly higher DNA damage level than healthy controls (both p<0.05/6). DNA damage level was comparable between hepatitis C (+) subjects without renal disease and HCV (+) hemodialysis subjects, and between hemodialysis subjects with and without hepatitis C infection (all p>0.05/6). Linear regression analysis revealed that hepatitis C infection was the only independent factor in predicting the peripheral DNA damage (p<0.05, beta=0.395). Each one of end-stage renal disease and hepatitis C infection significantly increases DNA damage level. However, in hemodialysis subjects, hepatitis C infection does not cause significant additional increase in DNA damage level, and it may be partly due to protective effect of hemodialysis on hepatitis C infection.     

Bioinformatics Analysis of Domain 1 of HCV-Core Protein: Iran

International Journal of Peptide Research and Therapeutics - Hepatitis C virus (HCV) infection is a serious global health problem and a cause of chronic hepatitis, liver cirrhosis, and...     

Hepatitis C in India

Hepatitis C is an emerging infection in India and an important pathogen causing liver disease in India. The high risk of chronicity of this blood-borne infection and its association with hepatocellular carcinoma underscores its public health importance. Blood transfusion and unsafe therapeutic interventions by infected needles are two preventable modalities of spread of hepatitis C infection. In addition, risk factor modification by reducing the number of intravenous drug users will help curtail the prevalence of this infection. This review summarizes the extent, nature and implications of this relatively new pathogen in causing disease in India.     

Serum cytokine levels as putative prognostic markers in the progression of chronic HCV hepatitis to cirrhosis

Hepatitis C virus (HCV) infection can present as an acute manifestation, and can lead to severe complications such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). It represents a global health problem because there is no vaccine currently available. Cytokines play an important role in viral clearance, infection control, inflammation, regeneration and fibrosis, and also are implicated in the pathological processes occurring in the liver during viral infection. Immunological markers of chronic HCV hepatitis progression as compared to cirrhosis and HCC would be extremely useful, particularly for distinguishing between the molecules produced during HCV-induced chronic inflammation and those secreted during cirrhosis and HCC. In this work, we evaluated the serum levels of several cytokines, chemokines and growth factors in 30 patients affected by chronic HCV (HC), 30 patients affected by HCV-related cirrhosis (LC) and 20 healthy, control subjects. We used a multiplex biometric ELISA-based immunoassay in order to identify molecules that might be useful for monitoring the progression of HCV to liver cirrhosis and, possibly, to cancer. Our results show that some pro-inflammatory molecules are significantly up-regulated, and play a role as immunological markers in the intermediate steps towards liver cancer, and that hepatocyte growth factor (HGF) is a specific marker of liver cirrhosis. Finally, these data will be used to define a cytokinome profile, which might prove useful for studies involving the transition of chronic inflammation to neoplastic processes.     

Sexual transmission of hepatitis C virus and its relation with hepatitis B virus and HIV.

OBJECTIVE--To determine the extent of transmission of hepatitis C virus in sexual partners of intravenous drug misusers and to examine the relation between the prevalences of HIV, hepatitis B virus, and hepatitis C virus infections in homosexual men and intravenous drug misusers and their sexual partners. DESIGN--Serum samples collected between 1984 and 1988 were tested for hepatitis B virus markers and antibodies against hepatitis C virus by enzyme linked immunosorbent assay (ELISA) and for HIV antibody by enzyme immune analysis and western blotting. SETTING--Large referral university hospital with an external AIDS clinic in the metropolitan area of Barcelona, Spain. SUBJECTS--243 Intravenous drug misusers, 143 of their regular heterosexual partners, and 105 homosexual men. MAIN OUTCOME MEASURES--Prevalences of hepatitis C virus, hepatitis B virus, and HIV infections. RESULTS--In all, 178 of the 243 (73%) intravenous drug misusers, 16 out of 143 (11%) of their partners, and 17 of the 105 (16%) homosexual men had antibodies against hepatitis C virus. The presence of hepatitis C virus infection was unrelated to sex, age, the presence of HIV or hepatitis B virus infections, or the Centers for Disease Control stage of HIV. In sexual partners of intravenous drug misusers there were strong correlations between the presence of hepatitis C virus infection and that of HIV (p = 0.001) and hepatitis B virus (p = 0.013) infections. CONCLUSIONS--Intravenous drug misusers have a high risk of acquiring hepatitis C virus, hepatitis B virus, and HIV infections, but the presence of hepatitis C virus infection seems to be unrelated to the presence of the other two viruses. Homosexual men have a high prevalence of HIV and hepatitis B virus infections with a low prevalence of hepatitis C virus infection, the presence of which is not related to that of the other two infections. Conversely, heterosexual partners of intravenous drug misusers have low prevalences of the three virus infections, but the presence of hepatitis C virus infection correlates significantly with the presence of HIV and hepatitis B infections. The rate of sexual transmission of hepatitis C virus seems to be low, even in partners of people known to be seropositive for this virus.     

丙型肝炎病毒感染与肝细胞癌相关关系的研究进展

世界上有数亿的人口患有丙型肝炎,而丙型肝炎病毒(HCV)的感染易转为慢性,引起肝细胞炎性坏死及再生,导致肝纤维化、硬化甚至肝细胞癌(HCC),是危害人类健康的一个重要卫生问题。HCV的感染可导致HCC的发生,但HCV相关性HCC的发生机制尚不清楚。免疫逃避机制是感染慢性化的一个重要原因,病毒通过其基因组编码的蛋白使肝细胞发生转化,可能是肝细胞癌变的重要机制。     

Immune responses in hepatitis C virus infection: the role of dendritic cells

Cellular immune responses are critical for the clearance of hepatitis C virus. Persistent infection results from a narrow and weak cellular immune response, in direct contrast to the broad, strong response associated with viral clearance in acute infection. The presence of dendritic cells in the liver facilitates presentation of viral antigens to both CD4+ and CD8+ T cell populations. Exploiting the potent antigen presentation capability of dendritic cells for immunotherapy of chronic hepatitis C is attractive; however, infection or transfection of segments or the entire hepatitis C virus genome appears to impair the allostimulation capacity of dendritic cells. If dendritic cell immunotherapy for hepatitis C virus infection is to become a reality, the mechanism behind the defective allostimulatory capacity needs to be deciphered.     

激活补体类乙型肝炎病毒表面抗原(HBsAg)循环免疫复合物在急慢性乙型肝炎中的意义

激活补体类HBsAg循环免疫复合物(HBsAg/C3-CIC )的检出率,与HBV复制标志的关系,在急慢性乙型肝炎病毒感染中表现不同。在慢性肝病(包括慢性迁延性乙型肝炎、慢性活动性乙型肝炎、乙型肝炎后肝硬化和HBV感染指标阳性的原发性肝癌)患者中,HBeAg阳性者,其HBsAg/C3-CIC的检出率显著高于HBeAg阴性者,且随HBeAgS/N值的升高而增加。在由HBV e系统组合成的四种模式中,单纯HBeAg阳性模式的检出率显著高于其它三种模式;在多聚白蛋白受体(PHSAr)阳性者中检出率显著高于PHSAr阴性者。而急性乙型肝炎(AH)的HBsAg/C3-CIC检出率无类似差异。这些结果提示,HBsAg/C3-CIC在HBV感染的急慢性肝病中具有不同的病理生理意义。     

High Rates of Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection in People Who Inject Drugs: A Prospective Cohort Study

Hepatitis C virus reinfection and spontaneous clearance of reinfection were examined in a highly characterised cohort of 188 people who inject drugs over a five-year period. Nine confirmed reinfections and 17 possible reinfections were identified (confirmed reinfections were those genetically distinct from the previous infection and possible reinfections were used to define instances where genetic differences between infections could not be assessed due to lack of availability of hepatitis C virus sequence data). The incidence of confirmed reinfection was 28.8 per 100 person-years (PY), 95%CI: 15.0-55.4; the combined incidence of confirmed and possible reinfection was 24.6 per 100 PY (95%CI: 16.8-36.1). The hazard of hepatitis C reinfection was approximately double that of primary hepatitis C infection; it did not reach statistical significance in confirmed reinfections alone (hazard ratio [HR]: 2.45, 95%CI: 0.87-6.86, p=0.089), but did in confirmed and possible hepatitis C reinfections combined (HR: 1.93, 95%CI: 1.01-3.69, p=0.047) and after adjustment for the number of recent injecting partners and duration of injecting. In multivariable analysis, shorter duration of injection (HR: 0.91; 95%CI: 0.83-0.98; p=0.019) and multiple recent injecting partners (HR: 3.12; 95%CI: 1.08-9.00, p=0.035) were independent predictors of possible and confirmed reinfection. Time to spontaneous clearance was shorter in confirmed reinfection (HR: 5.34, 95%CI: 1.67-17.03, p=0.005) and confirmed and possible reinfection (HR: 3.10, 95%CI: 1.10-8.76, p-value=0.033) than primary infection. Nonetheless, 50% of confirmed reinfections and 41% of confirmed or possible reinfections did not spontaneously clear. Conclusions: Hepatitis C reinfection and spontaneous clearance of hepatitis C reinfection were observed at high rates, suggesting partial acquired natural immunity to hepatitis C virus. Public health campaigns about the risks of hepatitis C reinfection are required.     

Immunopathogenesis of hepatitis C virus infection

Hepatitis C virus, a recently identified member of the family Flaviviridae, is an important cause of chronic viral hepatitis and cirrhosis. There are similarities in the nature of the immune response to this pathogen with immunity in other flavivirus and hepatotropic virus infections, such as hepatitis B. However, the high rate of viral persistence after primary hepatitis C infection, and the observation that neutralizing antibodies are not protective, would suggest that there are a number of important differences between hepatitis C, other flaviviruses, and hepatitis B. The phenomenon of quasispecies evolution and other viral factors have been proposed to contribute to immune evasion by hepatitis C virus. In the face of established persistent infection, virus-specific cytotoxic T lymphocytes may exert some control over viral replication. However, these same effectors may also be responsible for the progressive liver damage characteristic of chronic hepatitis C infection. The nature of protective immunity, including the role of innate immune responses early after hepatitis C exposure, remains to be defined.     

Hepatitis B viral factors and clinical outcomes of chronic hepatitis B

Hepatitis B virus (HBV) infection is an important health problem and the major cause of chronic hepatitis, cirrhosis as well as hepatocellular carcinoma (HCC) worldwide. The natural history of chronic HBV infection can be divided into 4 dynamic phases in HBV carriers who acquire the virus early in life. In general, the frequency and severity of hepatitis flares in the immune clearance or reactivation phase predict disease progression in HBV carriers, and early HBeAg seroconversion typically confers a favorable outcome. In contrast, late or absent HBeAg seroconversion after multiple hepatitis flares accelerates the progression of chronic hepatitis to cirrhosis. Recently, several hepatitis B viral factors predictive of clinical outcomes have been identified. For example, serum HBV DNA level at enrollment is the best predictor of adverse outcomes (cirrhosis, HCC and death from liver disease) in adults with chronic HBV infection. In addition, HBV genotype C, basal core promoter (BCP) mutant and pre-S deletion mutant are associated with increased risk of HCC development. In conclusion, hepatitis B viral factors such as serum HBV DNA level, genotype and mutants have already been clarified to influence disease progression of chronic hepatitis B. Further studies are needed to investigate the pathogenic mechanism of each viral factor.