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ABSTRACT: CD55 limits excessive complement activation on the host cell surface by accelerating the decay of C3 convertases. In this study, we observed that hepatitis C virus (HCV) infection of hepatocytes or HCV core protein expression in transfected hepatocytes upregulated CD55 expression at the mRNA and protein levels. Further analysis suggested that HCV core or full-length (FL) genome enhanced CD55 promoter activity in a luciferase based assay, which is further augmented in the presence of IL-6. Mutation of the CREB or SP-1 binding site on the CD55 promoter impaired HCV core mediated upregulation of CD55. HCV infected or core transfected Huh7.5 cells displayed greater cell viability in the presence of CD81 and CD55 antibodies and complement. Biochemical analysis revealed that CD55 was associated with cell culture grown HCV after purification by sucrose density gradient ultracentrifugation. Consistent with this, a polyclonal antibody to CD55 captured cell culture grown HCV. Blocking antibodies against CD55 or virus envelope glycoproteins in the presence of normal human serum as a source of complement inhibited HCV infection. The inhibition was enhanced in the presence of both the antibodies and serum complement. Collectively, these results suggest that HCV induces and associates with a negative regulator of the complement pathway, a likely mechanism for immune evasion.
Journal of Virology 05/2013; · 5.40 Impact Factor
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ABSTRACT: The instability of recombinant clones accommodating large or full-length viral genomes is frequently a technical challenge in RNA virus research. In an attempt to establish a rapid plasmid-based reverse genetics system that utilizes long RT-PCR technique (LRP), similar difficulty was encountered in the cloning of 9022-bp LRP amplicon. All HCV genotype 1a strains used for LRP cloning showed a remarkable difference in terms of cloning stability. Subsequent analysis revealed the predictive value of phylogenetic positions in determining the cloning stability. Putative E. coli promoters on the HCV genome might be responsible for such cloning difference. An exhaustive exploration, testing nearly one hundred cloning protocols, did not reveal a general approach that can achieve stable cloning for all HCV 1a strains. The selection of appropriate strains, guided by phylogenetic analysis, appears to be necessary prior to the construction of infectious HCV 1a clones. These observations are not only valuable for potentially establishing an HCV 1a cell culture model but also have general implications for other RNA viruses due to concern about cloning instability.
Journal of virological methods 04/2013; · 2.13 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) proteins inhibit complement component expression, which may attenuate immunity against infection. In this study, we examined whether HCV regulates membrane attack complex (MAC) via complement component C9. MAC is composed of C5b- 9, and mediates cell lysis of invaded pathogens. Liver biopsy specimens from chronically HCV infected patients exhibited a lower level of C9 mRNA expression as compared to liver biopsy specimens from unrelated disease, or healthy control human liver RNA. Hepatocytes infected with cell culture grown HCV or expressing HCV core protein also displayed significant repression of C9 mRNA and protein levels. Promoter analysis suggested TCF-4E transcription factor is responsible for HCV core mediated C9 promoter regulation. Sera from chronically HCV infected patients displayed a lower C5b-9 level and a reduced antimicrobial effect on model organisms, as compared to unrelated patient sera or sera from healthy volunteers. Together, these results on C9 regulation by HCV core protein coupled with functional impairment of membrane attack complex underscore HCV mediated attenuation of immune mechanisms.
Journal of Virology 03/2013; · 5.40 Impact Factor
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ABSTRACT: Chronic hepatitis C Virus (HCV) infection is one of the major causes of liver fibrosis and liver transplantation in the United States. Circulating microRNA (miRNA) in the blood are emerging as biomarkers for pathological conditions. In the present study, we performed a systematic screening approach to identify upregulated miRNAs in the plasma/serum of HCV infected patients with different stages of hepatic histological disease severity. We initially screened serum samples of HCV infected patientswith fibrosisand compared with sera of healthy volunteers using serum miRNA array profiling, and identified a group of modulated miRNAs. Subsequent study demonstrated that miR-20aand miR-92a in HCV infected fibrosispatients sera were significantly upregulated when compared with that of healthy volunteers or non-HCV associated liver disease. We have also observed anincrease of plasma miR-20a and miR-92a in acute and chronic HCV infected patients as compared to that of healthy volunteers. However, there was no correlation between the plasma/serum levels of any of these miRNAs with HCV viral loads.We next investigated longitudinal plasma samples from HCV infected patients. Our results suggested that miR-20a and miR-92a remained unaltered in HCV infected patients who progressed from acute to chronic infection. On the other hand, miR-92a expression was reduced in acute to resolved individuals. These data provide evidence that plasma/serumlevels of miR-20a and miR-92a have potential as sensitive and cost effective biomarkers for early detectionof HCV infection. Conclusion: The circulating miR-20a may serve as a potential for predictive biomarker in HCV mediated fibrosis. (HEPATOLOGY 2013.).
Hepatology 02/2013; · 11.66 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) mediated liver disease progression may reflect distinct molecular mechanisms for increased hepatocyte growth and hepatic stellate cell activation. In this study, we have observed that primary human hepatocytes; when infected in vitro with cell culture grown HCV genotype 1a or 2a, display viral RNA and protein expression. Infected hepatocytes displayed fibroblast like shape and extended life span. To understand the changes at the molecular level, we examined for epithelial-mesenchymal (EMT) markers. An increased mRNA and protein expression of vimentin, snail, slug and twist; and a loss of the epithelial cell marker E-cadherin, were observed. Snail and twist; when examined separately, were upregulated in chronically HCV infected liver biopsy specimens; indicating an onset of an active EMT state in infected liver. An increased expression of FSP-1 in the infected hepatocytes was also evident indicating a type 2 EMT state. Infected hepatocytes significantly increased phosphorylated β-catenin (Ser(552)) as an EMT mediator; which translocated into the nucleus, and activated Akt. Phosphorylation status of β-catenin at Thr(41)/Ser(45) moieties was specifically higher in control; as compared to HCV infected hepatocytes, implicating inactivation of β-catenin. Together, these results suggested that primary human hepatocytes infected with cell culture grown HCV, display EMT via activation of the Akt/β-catenin signaling pathway. This observation may have implications for liver disease progression and therapeutic intervention strategy using inhibitory molecules.
Journal of Virology 10/2012; · 5.40 Impact Factor
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ABSTRACT: We have examined the underlying mechanism of hepatitis C virus (HCV)-mediated IFITM1 regulation. IFITM1 is a potential target of miR-130a. Our results demonstrated that miR-130a expression was significantly higher in HCV-infected hepatocytes and liver biopsy specimens than in controls. Introduction of anti-miR-130a in hepatocytes increased IFITM1 expression. Hepatocytes stably expressing IFITM1 reduced HCV replication. Together, these results suggested that HCV infection of hepatocytes upregulates miR-130a and that use of anti-miR-130a may have potential for restriction of HCV replication.
Journal of Virology 07/2012; 86(18):10221-5. · 5.40 Impact Factor
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ABSTRACT: Hepatocytes are the main source of hepatitis C virus (HCV) replication and contain the maximum viral load in an infected person. Chronic HCV infection is characterized by weak cellular immune responses to viral proteins. Cathepsin S is a lysosomal cysteine protease and controls HLA-DR-antigen complex presentation through the degradation of the invariant chain. In this study, we examined the effect of HCV proteins on cathepsin S expression and found it to be markedly decreased in dendritic cells (DCs) exposed to HCV or in hepatocytes expressing HCV proteins. The downregulation of cathepsin S was mediated by HCV core and NS5A proteins involving inhibition of the transcription factors interferon regulatory factor 1 (IRF-1) and upstream stimulatory factor 1 (USF-1) in gamma interferon (IFN-γ)-treated hepatocytes. Inhibition of cathepsin S by HCV proteins increased cell surface expression of the invariant chain. In addition, hepatocytes stably transfected with HCV core or NS5A inhibited HLA-DR expression. Together, these results suggested that HCV has an inhibitory role on cathepsin S-mediated major histocompatibility complex (MHC) class II maturation, which may contribute to weak immunogenicity of viral antigens in chronically infected humans.
Journal of Virology 07/2012; 86(18):9919-28. · 5.40 Impact Factor
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Chihiro Morishima,
Mitchell L Shiffman,
Jules L Dienstag,
Karen L Lindsay,
Gyongyi Szabo,
Gregory T Everson,
Anna S Lok, Adrian M Di Bisceglie,
Marc G Ghany,
Deepa Naishadham,
Timothy R Morgan,
Elizabeth C Wright
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ABSTRACT: OBJECTIVES:During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.METHODS:Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.RESULTS:Among 657 patients who received full-dose peginterferon/ribavirin "lead-in" therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3-4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.CONCLUSIONS:Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.Am J Gastroenterol advance online publication, 12 June 2012; doi:10.1038/ajg.2012.137.
The American Journal of Gastroenterology 06/2012; · 7.28 Impact Factor
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ABSTRACT: The third component of human complement (C3) plays a central role in innate immune function as its activation is required to trigger classical as well as alternative complement pathways. In this study, we have observed that sera from patients chronically infected with hepatitis C virus (HCV) displayed significantly lower C3 levels than sera from healthy individuals. Liver biopsy specimens from the same patients also exhibited lower C3 mRNA expression than liver tissues from healthy donors. C3 mRNA level was reduced in hepatocytes upon infection with cell culture-grown HCV genotype 1a or 2a in vitro. Further analysis suggested that HCV core protein displayed a weak repression of C3 promoter activity by downregulating the transcription factor farnesoid X receptor (FXR). On the other hand, HCV NS5A protein strongly downregulated C3 promoter activity at the basal level or in the presence of interleukin-1β (IL-1β) as an inducer. In addition, the expression of the transcription factor CAAT/enhancer binding protein beta (C/EBP-β), which binds to the IL-1/IL-6 response element in the C3 promoter, was inhibited in liver biopsy specimens. Furthermore, expression of C/EBP-β was reduced in hepatocytes infected with cell culture-grown HCV, as well as in hepatocytes transfected with the NS5A genomic region of HCV. Together, these results underscore the role of HCV NS5A protein in impairing innate immune function.
Journal of Virology 12/2011; 86(4):2221-8. · 5.40 Impact Factor
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ABSTRACT: Prospective studies of serum hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C are lacking. The aim of this study was to determine the frequencies and performance of elevated α-fetoprotein (AFP), AFP-L3, and des-γ-carboxy prothrombin (DCP) levels as HCC biomarkers in advanced hepatitis C.
Patients in the HALT-C Trial were tested every 3 months for 42 months. Screening ultrasound was performed every 12 months. Levels of biomarkers were compared in patients in whom HCC did or did not develop.
In all, 855 patients were evaluated; HCC developed in 46. Among patients without HCC, 73.2% had AFP consistently <20, 24.5% had at least one AFP between 20 and 199, and 2.3% had at least one AFP value ≥200 ng/ml; 73.7% had DCP consistently <90, 11.6% had at least one DCP between 90 and 149, and 14.7% had at least one DCP value ≥150 mAU/ml. AFP-L3 ≥10% was present at least once in 9.0% and in 17.1% of those with AFP ≥20 ng/ml. Among all patients with elevated biomarkers, a diagnosis of HCC was made in 0-31.6% (depending on the biomarker and cutoff) during the subsequent 24 months. AFP ≥200 ng/ml had the highest specificity (99%), but sensitivity was ≤20%. DCP ≥40 mAU/ml had the highest sensitivity (76%), but specificity was ≤58%. Independent predictors of elevated AFP were gender (female), race (Black), more advanced disease, and HCC. Elevated DCP was associated with more advanced disease and HCC.
Mild-moderate elevations in total AFP and DCP but not in AFP-L3 occur frequently in patients with chronic hepatitis C and advanced fibrosis, are related to factors other than HCC, and are poor predictors of HCC.
The American Journal of Gastroenterology 09/2011; 107(1):64-74. · 7.28 Impact Factor
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Xiaoan Zhang,
Soo Hyung Ryu,
Yanjuan Xu,
Tamerl Elbaz,
Abdel-Rahman N Zekri,
Ashraf Omar Abdelaziz,
Mohamed Abdel-Hamid,
Valerie Thiers,
Santiago F Elena,
Xiaofeng Fan, Adrian M Di Bisceglie
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ABSTRACT: Hepatitis C virus (HCV) infection is a well-documented etiological factor for hepatocellular carcinoma (HCC). As HCV shows remarkable genetic diversity, an interesting and important issue is whether such a high viral genetic diversity plays a role in the incidence of HCC. Prior data on this subject are conflicting.
Potential association between HCV genetic mutations or strain variability and HCC incidence has been examined through a comparative genetic analysis merely focused on a single HCV subtype (genotype 4a) in a single country (Egypt).
The study focused on three HCV sequence datasets with explicit sampling dates and disease patterns. An overlapping HCV Core/E1 domain from three datasets was used as the target for comparative analysis through genetic and phylogenetic approaches.
Based on partial Core/E1 domain (387 bp), genetic and phylogenetic analysis did not identify any HCC-specific viral mutations and strains, respectively.
The Core/E1 domain of HCV genotype 4a in Egypt does not contain HCC-specific mutations or strains. Additionally, sequence errors resulting from the polymerase chain reaction, together with a strong evolutionary pressure on HCV in patients with end-stage liver disease, have significant potential to bias data generation and interpretation.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 09/2011; 52(4):333-8. · 3.12 Impact Factor
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ABSTRACT: Quasispecies is a remarkable characteristic of hepatitis C virus (HCV) and has profound roles in HCV biology and clinical practice. The understanding of HCV quasispecies behavior, in particular in acute HCV infection, is valuable for vaccine development and therapeutic interference. However, acute HCV infection is seldom encountered in clinic practice due to its silent onset. In the present study, we reported a unique case of de novo HCV infection associated with the transplantation of bone marrow from a HCV-positive donor. HCV quasispecies diversity was determined in both the donor and the recipient over a 4-year follow-up, accompanied with simultaneous measurement of HCV neutralizing antibody. Detailed genetic and phylogenetic analyses revealed a divergent quasispecies evolution, which was not related to dynamic changes of HCV neutralizing antibody. Instead, our data suggested an essential role of the fitness adaptation of founder viral population in driving such an evolutionary pattern.
Biochemical and Biophysical Research Communications 09/2011; 414(1):148-52. · 2.48 Impact Factor
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Ira M Jacobson,
John G McHutchison,
Geoffrey Dusheiko, Adrian M Di Bisceglie,
K Rajender Reddy,
Natalie H Bzowej,
Patrick Marcellin,
Andrew J Muir,
Peter Ferenci,
Robert Flisiak, [......],
Ricard Sola,
Ruben A Terg,
Eric M Yoshida,
Nathalie Adda,
Leif Bengtsson,
Abdul J Sankoh,
Tara L Kieffer,
Shelley George,
Robert S Kauffman,
Stefan Zeuzem
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ABSTRACT: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients.
In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response).
Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.
Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).
New England Journal of Medicine 06/2011; 364(25):2405-16. · 53.30 Impact Factor
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Jules L Dienstag,
Marc G Ghany,
Timothy R Morgan, Adrian M Di Bisceglie,
Herbert L Bonkovsky,
Hae-Young Kim,
Leonard B Seeff,
Gyongyi Szabo,
Elizabeth C Wright,
Richard K Sterling,
Gregory T Everson,
Karen L Lindsay,
William M Lee,
Anna S Lok,
Chihiro Morishima,
Anne M Stoddard,
James E Everhart
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ABSTRACT: The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years. Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. Six hundred seventy-nine clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5% per year) than subjects with fibrosis (3.3% per year) (P<0.0001). Child-Turcotte-Pugh (CTP) score≥7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a CTP score≥7, the rate of subsequent events increased to 12.9% per year, including a death rate of 10% per year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis. CONCLUSION: Among patients with advanced hepatitis C who failed peginterferon and ribavirin therapy, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once the CTP score reaches at least 7.
Hepatology 04/2011; 54(2):396-405. · 11.66 Impact Factor
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Adrian M Di Bisceglie,
Anne M Stoddard,
Jules L Dienstag,
Mitchell L Shiffman,
Leonard B Seeff,
Herbert L Bonkovsky,
Chihiro Morishima,
Elizabeth C Wright,
Kristin K Snow,
William M Lee,
Robert J Fontana,
Timothy R Morgan,
Marc G Ghany
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ABSTRACT: Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon. CONCLUSION: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.
Hepatology 04/2011; 53(4):1100-8. · 11.66 Impact Factor
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Leonard B Seeff,
Gregory T Everson,
Timothy R Morgan,
Teresa M Curto,
William M Lee,
Marc G Ghany,
Mitchell L Shiffman,
Robert J Fontana, Adrian M Di Bisceglie,
Herbert L Bonkovsky,
Jules L Dienstag
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 03/2011; 9(3):278-9. · 5.64 Impact Factor
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ABSTRACT: Previous studies have suggested that prior exposure to hepatitis B virus (HBV) infection may increase the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The aim of this study was to compare the prevalence of previous or occult HBV infection in a cohort of hepatitis B surface antigen-negative patients with histologically advanced chronic hepatitis C in the United States who did or did not develop HCC. Stored sera from 91 patients with HCC and 182 matched controls who participated in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial were tested for hepatitis B core antibody (anti-HBc), hepatitis B surface antibody, and HBV DNA. Frozen liver samples from 28 HCC cases and 55 controls were tested for HBV DNA by way of real-time polymerase chain reaction. Anti-HBc (as a marker of previous HBV infection) was present in the serum of 41.8% HCC cases and 45.6% controls (P=0.54); anti-HBc alone was present in 16.5% of HCC cases and 24.7% of controls. HBV DNA was detected in the serum of only one control subject and no patients with HCC. HBV DNA (as a marker of occult HBV infection) was detected in the livers of 10.7% of HCC cases and 23.6% of controls (P=0.18). CONCLUSION: Although almost half the patients in the HALT-C Trial had serological evidence of previous HBV infection, there was no difference in prevalence of anti-HBc in serum or HBV DNA in liver between patients who did or did not develop HCC. In the United States, neither previous nor occult HBV infection is an important factor in HCC development among patients with advanced chronic hepatitis C.
Hepatology 03/2011; 54(2):434-42. · 11.66 Impact Factor
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ABSTRACT: Chronic hepatitis C virus (HCV) infection is a major cause of liver disease worldwide. HCV infection is currently treated with IFNα plus ribavirin for 24 to 48 weeks. This demanding therapy fails in up to 50% of patients, so the use of pharmacogenetic biomarkers to predict the outcome of treatment would reduce futile treatment of non-responders and help identify patients in whom therapy would be justified. Both IFNα and ribavirin primarily act by modulating the immune system of the patient, and HCV uses multiple mechanisms to counteract the antiviral effects stimulated by therapy. Therefore, response to therapy is influenced by variations in human genes governing the immune system and by differences in HCV genes that blunt antiviral immune responses. This article summarizes recent advances in understanding how host and viral genetic variation affect outcome of therapy. The most notable human associations are polymorphisms within the IL28B gene, but variations in human leukocyte antigen and cytokine genes have also been associated with treatment outcome. The most prominent viral genetic association with outcome of therapy is that HCV genotype 1 is much less sensitive to treatment than genotypes 2 and 3, but genetic differences below the genotype level also influence outcome of therapy, presumably by modulating the ability of viral genes to blunt antiviral immune responses. Pharmacogenetic prediction of the outcome of IFN-based therapy for HCV will require integrating the efficacies of the immunosuppressive mechanisms of a viral isolate, and then interpreting the viral resistance potential in context of the genetic profile of the patient at loci associated with outcome of therapy. Direct-acting inhibitors of HCV that will be used in combination with IFNα are nearing approval, so genetic prediction for anti-HCV therapy will soon need to incorporate viral genetic markers of viral resistance to the new drugs.
Genome Medicine 02/2011; 3(2):8.
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ABSTRACT: The fourth component of human complement (C4) plays an important role in innate immune function. C4 activity has been observed to be significantly lower in patients with chronic hepatitis C virus (HCV) infections, although the mechanism remains unknown. In this study, we have examined the mechanisms of C4 regulation by HCV. Liver biopsy specimens from patients with chronic HCV infections displayed significantly lower C4 mRNA levels than liver tissue samples from patients with unrelated liver disease. Further, C4 mRNA levels of the two isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with RNA from HCV genotype 1a or 2a. Subsequently, a significant C4 regulatory role of HCV core or NS5A upon C4 promoter activity was observed. HCV core or NS5A transgenic mice displayed a reduction in C4 mRNA. Gamma interferon (IFN-γ)-induced C4 promoter activation was also impaired in the presence of HCV proteins. We further demonstrated that HCV core reduced the expression of upstream stimulating factor 1 (USF-1), a transcription factor important for basal C4 expression. On the other hand, the expression of interferon regulatory factor 1 (IRF-1), which is important for IFN-γ-induced C4 expression, was inhibited by hepatocytes expressing HCV NS5A. These results underscore the roles of HCV proteins in innate immune regulation in establishing a chronic infection.
Journal of Virology 02/2011; 85(9):4157-66. · 5.40 Impact Factor
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Anna S Lok,
James E Everhart,
Elizabeth C Wright, Adrian M Di Bisceglie,
Hae-Young Kim,
Richard K Sterling,
Gregory T Everson,
Karen L Lindsay,
William M Lee,
Herbert L Bonkovsky,
Jules L Dienstag,
Marc G Ghany,
Chihiro Morishima,
Timothy R Morgan
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ABSTRACT: Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression. We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer posttreatment follow-up period.
The study included 1048 patients with chronic hepatitis C (Ishak fibrosis scores ≥ 3) who did not have a sustained virologic response (SVR) to therapy. They were randomly assigned to groups given a half-dose of peginterferon or no treatment (controls) for 3.5 years and followed up for a median of 6.1 (maximum, 8.7) years.
Eighty-eight patients developed HCC (68 definite, 20 presumed): 37 of 515 who were given peginterferon (7.2%) and 51 of 533 controls (9.6%; P = .24). There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples. After 7 years, the cumulative incidences of HCC in treated and control patients with cirrhosis were 7.8% and 24.2%, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.83); in treated and control patients with fibrosis, incidences were 8.3% and 6.8%, respectively (HR, 1.44; 95% CI, 0.77-2.69). Treated patients with a ≥ 2-point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores (2.9% vs 9.4%; P = .03).
Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVRs. Patients with cirrhosis who received peginterferon treatment had a lower risk of HCC than controls.
Gastroenterology 12/2010; 140(3):840-9; quiz e12. · 11.68 Impact Factor
