HCV: Virology and Pathogenesis
Sun, Nov 02 - 8:00 AM
Extrahepatic Manifestations
A. L. Klepper; J.
Garber; J. L. Walewski; J. A. Gutierrez; T. D. Schiano; A. D. Branch.
Background:
HCV replication has been reported in extrahepatic cells, however, ability to detect HCV RNA in these cells
often fluctuates. We tested the hypothesis that denaturation prior to RT/
Methods:
Mononuclear cells from ascitic fluid (AMCs;n=5)
and PMBCs (n=1) were isolated, cultured for 1-8 wks, and RNA was Trizol
extracted. Prior to RT/
Results:
4/5 of the
Discussion:
These studies suggest that much of the HCV RNA human cells is in dsRNA complexes, answering a persistently vexing
question in the investigation of (extrahepatic) HCV replication: Why it is so
difficult to consistently detect HCV RNA in infected cells and human specimens?
The answer: RNA is there, it is just present in structures that evade detection
by conventional RT/
HCV Drug Pipeline – Drug Resistance
A. U. Neumann.
Background:
Current paradigm assumes that HCV has no virological
mechanism to archive mutations and that resistant strains (
Methods:
A new mathematical model combining intra-cellular HCV
replication dynamics with cell infection dynamics is used. Intra-cellular RNA
(ICR) forms replication units (RU), which in turn synthesize more ICR that is
partially packaged and exported as virions.
Results:
Simulation of the ODE model shows that if
This dynamical archiving process, within a large range of
parameters, allows for establishment of relatively high level of
Conclusions:
In contradiction to the current paradigm, resistant HCV
strains can persist after the end of treatment with direct anti-virals by a
process of dynamical archiving, which is first described here allowing to calculate the conditions necessary to prevent it.
HCV Drug Pipeline – Nitazoxanide
1000.
Nitazoxanide Inhibits Hepatitis C Virus Replication In Vitro.
T. Schaninger; J.
Hong; G. G. Luo.
Background.
Nitazoxanide is a thiazolide anti-infective with activity
against a number of protozoa, bacteria, and viruses. It is FDA approved for
treatment of Cryptosporidium and Giardia. Nitazoxanide inhibits replication of
hepatitis C virus, hepatitis B virus, and rotavirus in vitro. Based on its
broad antiviral activity, the mechanism of action is likely through cellular
processes rather than specific antiviral targets. Rossignol and colleagues
recently reported that the use of nitazoxanide in combination with
peginterferon alfa-2a with or without ribavirin among treatment-naive hepatitis
C patients infected with genotype 4 significantly improved viral response
compared to the standard of care (peginterferon alfa-2a plus ribavirin). The
sustained virologic response was 79%, 61%, and 50% respectively.
Method.
We tested nitazoxanide and its active metabolite, tizoxanide,
in HCV cell culture. Time of addition experiments were carried out in the
infectious HCV genotype 2a (JFH1) cull culture model to investigate which steps
of the replicative cycle are inhibited by nitazoxanide.
Result.
Nitazoxanide and tizoxanide exhibited potent antiviral
activity against subgenomic HCV 1b replicon as well as infectious HCV genotype
2a (JFH1). Nitazoxanide and tizoxanide significantly inhibited HCV infection
when they were added during the infection period. However, they showed reduced
activity when added post infection.
Conclusion.
These findings indicate thiazolide affects the early stage of
the HCV infection cycle. A proposed mechanism of action of nitazoxanide against
HCV replication will be described and discussed.
HIV/HBV Coinfection
1002. HBV-HCV
Coinfection: Insights from a Novel Model System.
P. Bellecave; J.
Gouttenoire; M. Gajer; V. Brass; G. Koutsoudakis; H. E. Blum; M. Nassal; R.
Bartenschlager; D. Moradpour.
Background:
Coinfection with hepatitis B virus (HBV) and hepatitis C
virus (HCV) has been associated with severe liver disease and frequent
progression to liver cirrhosis and hepatocellular carcinoma. Clinical evidence
suggests reciprocal replicative suppression of the two viruses ('viral
interference'). However, virtually nothing is known about molecular
interactions between HBV and HCV due to the lack of appropriate model systems.
Methods:
A tetracycline-regulated gene expression system was used to generate
a panel of stable Huh-7 cell lines inducibly replicating HBV. These cell lines
and control Huh-7 cell lines inducibly expressing the green fluorescent protein
(GFP) were transfected with selectable HCV replicons or infected with cell
culture-derived HCV (HCVcc).
Results:
Three successive transfection and selection steps allowed the
establishment of Huh-7 cells inducibly replicating HBV and constitutively
replicating subgenomic HCV RNA. In these cell lines, it is possible to regulate
the expression of HBV proteins, HBV genome replication, and infectious viral
particle formation by the concentration of tetracycline in the culture medium
while HCV proteins are expressed and HCV RNA replicated constitutively. The
presence or absence of replicating HBV did not influence the antiviral effect
of interferon-alpha against HCV. In addition, specific inhibition of one virus
did not significantly affect gene expression, replication and release of the
other. Experiments using HCVcc did not reveal any significant superinfection
exclusion of HCV by HBV. Finally, cell culture-adapted HCVcc isolated from
long-term cultures did not display any HBV-specific adaptation.
Conclusion:
HBV and HCV can replicate in the same cell without any
significant direct interaction. Therefore, the viral interference observed in
vivo in coinfected patients is likely due to innate and/or adaptive host immune
responses. These findings provide new insights into the pathogenesis of HBV-HCV
coinfection and may contribute in the future to its clinical management.
Epidemiology/Transmission – General
K. Goto; Y. Tanaka; T.
Endo; K. Ito; A. A. Khan; M. Mizokami.
Background/Aim:
The incidence of mother-to-infant transmission is
approximately 5–10% in infants born to HCV-RNA-positive mothers. This is an
important route of HCV infection in childhood because HCV infection through
blood transfusion has been effectively managed by blood donor screening. Many
data are available for HCV evolution in adults but there is little information
regarding the HCV evolutionary mechanism in mothers and their infants who got
infection by vertical transmission. Our aims are to investigate the vertical
transmission and characteristics of HCV evolution of mother–to-infant pairs.
Methods:
Seven Japanese mother-to-infant pairs with vertical
transmission of HCV were studied. The 336-bp sequences in the NS5b gene, which
is an essential viral replicating enzyme encoding the viral RNA-dependent RNA
polymerase, were determined from serum samples at 2-6 points (~12.0 years intervals) in each patient. The sequences were
phylogenetically analyzed and the evolution of HCV was compared between mothers
and their infants.
Results:
The distribution of HCV subtypes in pairs was as follows: 3
pairs with 1b; 3 pairs with 2a; and 1 pair with 2b. The sequences obtained from
each pair were clustering together in a phylogenetic tree, providing evidence
of vertical transmission with a 97.3-99.7% identity of sequences of infants
with their respective mothers. Examining the evolution of HCV in each patient,
nucleotide substitutions within the NS5b region were identified in 4 of 7
mothers (0.26-4.46 x 10^-3 substitutions/site/year). Except for one infant who
showed a nucleotide substitution rate of 0.37 x 10^-3 /site/year, substitutions
were not found in other 5 infants during a follow-up of ~12.0 years.
Conclusions:
The study provides evidence of vertical transmission of HCV
from HCV-RNA-positive mothers to their infants. Less evolution of HCV observed
in infants may be due to low selective immunological pressure generated by the
infant host, as compared to HCV evolution in adults.
HCV Drug Pipeline – Telaprevir
1011. Long
term follow up of patients previously treated with telaprevir.
N. Forestier; S.
Susser; M. W. Welker; U. Karey; S. Zeuzem; C. Sarrazin.
Background:
Telaprevir (TVR) is a highly selective inhibitor of the
hepatitis C virus NS3/4A protease with blocking of HCV replication in patients
with hepatitis C. In this study, we describe the follow up status of patients
who were initially treated with telaprevir. So far, little is known, about what
happens after stopping treatment with TVR.
Methods:
We followed up patients with HCV who were treated in a phase
1b study for 14 days with TVR (monotherapy study, n=34) and in addition
patients who were treated in another study for 14 days with either TVR alone,
TVR+peginterferon or with placebo+peginterferon (combination study, n=20). Most
of the patients from the monotherapy study received no further treatment after
the 14 days treatment with TVR, however nearly all of the patients from the
combination study received after the initial 14 days treatment with TVR
standard of care treatment (
Results:
From the monotherapy study 5 patients were enrolled and all
patients showed TVR resistant variants during the initial treatment with TVR.
Patient 1 received no further treatment afterwards and 9 months after
Conclusions:
Variable outcomes have been detected in patients treated with
telaprevir alone or in combination with Peg-IFN for 14 days in phase 1 studies.
A detailed virologic status of the patients as well as sequencing analyses
results in these patients will be presented at the meeting.
HCV Treatment – Predictors of Treatment
Response
1019.
Hepatitis C Viral Genotype Age is a Predictor of the Clinical Response to
Interferon Therapy.
P.
S. Pang; P. J. Planet; J. S. Glenn.
Purpose:
To determine why patients infected with the
various hepatitis C viral genotypes require different durations of
therapy and achieve different sustained viral response rates to interferon plus
ribavirin therapy.
Methods:
The first phylogenetic analysis to include all available HCV
genomic sequences was performed. The resultant tree was then used, in
conjunction with a review of all prospective clinical trials that studied
interferon and ribavirin therapy, to determine if a correlation existed between
genomic age and clinical outcome. The viral loci potentially responsible for
interferon treatment sensitivity differences were then screened for using
ancestral protein sequence reconstruction.
Results:
A new cladogram of HCV was constructed, which, for the first
time reveals the relative evolutionary ages of all the major HCV genotypes. We
determined that genotype-specific clinical outcomes directly correlate with
genotype age. This relationship allowed us to predict that genotypes 5 and 6,
for which there currently are no published prospective trials, will likely have
intermediate response rates, similar to genotype 3. Two viral loci that likely
play a direct role in determining genotype-specific outcomes were also
identified. Prior studies have independently identified these exact two loci as
having a role in inhibiting the innate immune factor PKR.
Conclusion:
A primary determinant of genotype-specific response rates to
interferon therapy is a set of viral factors that evolved to progressively
acquire an increasing ability to inhibit the innate immune response.
HCV Disease Progression – Race
1022.
Severity of Liver Disease in Chronic Hepatitis C Patients: Latino versus
Caucasian.
M.
Y. Sheikh; M. H. Bashir; A. A. Afaq; H. Sadiq; J. Choudhury.
Background
Ethinicity can affect the natural history of chronic
hepatitis C (
Methods
The clinical data of 481 Caucasians and 472 Latinos with
Results
Of 481 Caucasians, 58.1% were males and 41.9% females with a
mean age of 46.8 years and mean
Conclusions
At the time of HCV diagnosis, Latinos have advanced stages of
hepatic fibrosis as compared to Caucasians, indicating higher disease
progression rates. There is a high prevalence of steatosis in Latinos as
compared to Caucasians. Further studies are needed to evaluate various factors
affecting the natural history in Latino patients with
|
Ethnicity |
0 |
1-2 |
3-4 |
Total |
|
Caucasian #(%) |
80(16.6%) |
298(62%) |
103(21.4%) |
481(100%) |
|
Latino # (%) |
85(18%) |
240(50.8) |
147(31.1%) |
472(100%) |
|
Total # (%) |
165(17.3%) |
538(56.5%) |
250(26.2%) |
953(100%) |
Disease Progression – Race
A. Afendy; M.
Stepanova; A. Baranova; N. Hossain; I. Younossi; A. M. Wheeler; Z. M. Younossi.
Background:
African American (AA) with CH-C have
lower response rates to pegylated interferon and Ribavirin (
Aims:
To compare gene expression of
Caucasians (CA) with CH-C to those of AA with CH-C.
Methods:
CH-C patients who were scheduled to receive
Results:
A total of 53 CH-C patients were included in this analysis.
Of these, 42 patients were CA and 11 were AA with CH-C (Age: 47.8±5.9, 58%
male, 74% genotype 1). Overall sustained virologic response was 45% in CA and
18% in AA. Prior to treatment, AA patients had lower expression of the
following genes: MMP9 (CA/AA: 1.373),
Conclusions:
AA CH-C patients seem to have significantly lower expression
of a number of genes involved in interferon signaling pathway, prior to and
shortly after initiation of
HIV/HCV Coinfection
N. I. Rallón; M.
López; V. Soriano; J. García-Samaniego; M. Romero; P. Labarga; J.
González-Lahoz; J. M. Benito.
Background:
Cellular responses against HCV seem to be low in most
patients with chronic hepatitis C. They may be even further impaired in HIV
patients. Herein, we examine the functional profile of HCV-specific T-cells and
the impact of HIV coinfection in patients with chronic hepatitis C.
Methods:
HCV-specific CD4+ and CD8+ T-cell responses were examined in
30 interferon-naive patients, 10 HCV-monoinfected and 20 HIV/HCV-coinfected.
The profile of cytokine production (IFN-γ, IL-2 and TNF-α) in
response to 324 genotype-matched overlapping peptides spanning five HCV
proteins (E2, p7, NS3, NS5a, NS5b) was measured using 5-colour flow cytometry.
Differences between groups for the different immune parameters were tested
using non-parametric tests.
Results:
CD4 counts and plasma HIV-RNA in coinfected patients were
390+213 cells/μl and 2.6+1.3 log copies/ml (65% of them were on HAART).
Serum HCV-RNA in monoinfected and coinfected patients was 5.7+0.8 and 6.4+0.7
log IU/ml, respectively (p=0.03). Overall, 90% of monoinfected patients had
genotype 1 whereas in coinfected patients 45% had HCV-1 and 55% had HCV-3.
The proportion of patients having a detectable CD4 or CD8
response against the five HCV proteins was high (>80%) and similar in both
mono- and coinfected patients. Levels of total CD4 and CD8 responses against
the five HCV proteins were also similar in both groups. The cytokine profile of
HCV-specific CD4 and CD8 T-cells was dominated, in both groups, by cells
producing only TNF-α. However, the contribution of single TNF-α+ cells to CD4 responses against NS3 and NS5a was
significantly higher in coinfected than in monoinfected patients. In contrast,
the contribution of cells producing only IL-2 into the CD4 response against the
different proteins was higher in monoinfected than in coinfected patients,
although differences did not reach statistical significance.
In HCV-1 patients there was a positive and significant
correlation between the contribution of single TNF-α+ cells to CD4
responses against NS5a and serum HCV-RNA, after adjusting for HIV load (r=0.86,
p=0.01).
Conclusions:
The functional profile of HCV-specific T-cells is limited to
a single function and dominated by TNF-α. The ability of CD4 T-cells to
produce IL-2 against HCV is impaired in HIV-coinfected patients. The greater
level of single TNF-α+ cells contributing to the CD4 response in
coinfected patients might explain at least in part a lower control of HCV
replication in this population.
Disease Progression –
1048. High
Incidence of Hepatocellular Carcinoma associated with Hepatitis C Virus
Genotype 3a in
A. A. Khan; Y. Tanaka;
Z. Azam; Z. Abbas; F. Kurbanov; S. S. Hamid; S. Jafri; M. Mizokami.
Background:
Infection with hepatitis C virus (HCV) genotype 1b is
reportedly associated with higher incidence of hepatocellular carcinoma (
Methods:
A total of 189 CLDs patients including 82 with
Results:
HCV-3a was the predominant genotype (81.4%) in the studied
cohort, followed by 3b (9.3%), 3k (2.3%), 1a (1.5%), 1c (1.5%), 1b (0.8%) and
2a (0.8%). The mean HCV RNA levels were significantly higher in
Conclusions:
HCV-3a having earlier epidemic spread in
HIV/HCV Coinfection
1053. Immune
restoration and HCV quasispecies evolution in HIV coinfected patients.
P. Vaghefi; G. Maurin;
D. Lavillette; C. Feray; E. Dussaix; A. Roque-Afonso.
Introduction:
HCV genetic variability is due to the high error rate of the
viral RNA polymerase and to negative and positive selection pressures. We
investigated the contribution of immune selection pressure on HCV quasispecies
evolution by studying the hypervariable region (HVR) in HIV co-infected
subjects upon immune restoration.
Patients and methods:
Twenty eight patients were studied at 2 time points: 15
patients before and after antiretroviral treatment initiation with a mean
interval of 24.3 +/- 10.6 months and 13 non-treated patients with a mean
interval of 18.1 +/- 12 months. Quasispecies complexity and its qualitative
modifications were assessed by SSCP and by cloning and sequencing. Analysis was
performed according to CD4 cell count, HIV and HCV viral load, HCV genotype,
aminotransferases levels (
Results:
In the treated group, CD4 cell count increased and HIV viral
load decreased significantly. A trend towards increased neutralizing activity
of sera was also observed. No significant change in HCV viremia and
quasispecies complexity was noted in both groups. Complexity was higher in the
14 patients infected by HCV genotype 1, particularly at the 2nd time point
(5.57 versus 3.5), independently of the viral load. Emergence of variants and
global modification of quasispecies (emergence + disappearing) was correlated
to the initial level of
Conclusion:
We had previously shown that qualitative variation of HVR was
not related to CD4 cell count and depended on the initial complexity
(Roque-Afonso, J Infect Dis 2002). Immune restoration, reflected by CD4 counts
increase, appears to be associated with an increase of neutralizing antibodies
titer, allowing the elimination of part of circulating variants, without any
impact on HCV viremia. In association with humoral response, the cellular
immunity also contributes to the quasispecies evolution as suggested by the
link between liver cytolysis and variants emergence.
Disease Progression
1057. Natural
history of HCV superinfection and reinfection.
P. A. White; J.
Grebely; J. K. Flynn; G. Matthews; M. K. Renkin; B. Yeung; W. Rawlinson; J.
Kaldor; M. Hellard; A. R. Lloyd; R. A. Ffrench; G. J. Dore.
Purpose:
To characterise the natural history
of HCV superinfection and reinfection.
Methods:
ATAHC is a prospective study of the natural history and
treatment of acute/early chronic HCV. Treated subjects received
Results:
167 subjects were enrolled, 107 received treatment. Nine
cases of superinfection (n=5) and reinfection (n=4) were identified, including
7 during (n=3, all superinfection) or following treatment (n=4, all
reinfection). 8 cases had ongoing injecting reported, 5 had temporal
Conclusion:
These findings describe a heterogeneous natural history of
HCV superinfection and reinfection, consistent with chimpanzee studies.
Protection from viral persistence upon reinfection can occur, but is not
universal.
Disease Progression
1062.
Hepatitis C as a risk factor for primary renal cell carcinoma.
S. C. Gordon; D.
Moonka; K. a. Brown; M. Y. Huang; S. E. Anteau; L. Lamerato.
Background:
Chronic HCV mediates the development of
Methods:
We used administrative data from a large integrated health
care system to explore the incidence of RCC among HCV infected persons. Adults
(over 18 yrs) testing HCV+ between 1997 and 2006 were compared to a control
cohort testing anti-HCV negative (HCV-) during the same time period; HBsAg and
HIV positive patients were excluded. Data from the system’s registry identified
all RCC pts diagnosed between 1997 and April 2008.
Results:
The cohort consisted of 74,570 pts with 12.6% HCV+ (n=9,401)
and 65,169 HCV negative. Males and African Americans (AA) had a higher
prevalence of HCV (15.4% males vs. 9.8% females, p<0.001 and 16.4% AA vs.
9.8% non-AA, p<0.001). The mean age of HCV+ patients was older than the HCV-
(52 vs. 48, p<0.001). There were 163 RCC patients (0.25/100) in the
unaffected vs. 35 (0.37/100) in the HCV+ group. The unadjusted OR for RCC was
1.49 (CI: 1.03, 1.83, p=0.03). The mean age at RCC diagnosis was much younger
in HCV+ individuals (52 vs. 63, p<0.001). When adjusting for age, race and
gender the overall OR for HCV among RCC patients was 1.2 (CI: 0.83, 1.74,
p=0.34). However, at particular risk were males less than age of 50 at HCV
diagnosis, where the adjusted OR for RCC was 4.8 (CI: 2.48, 9.17, p<0.001).
As expected, the risk of
Conclusions:
Chronic HCV is associated with a higher incidence of primary
renal cell carcinoma than non-infected persons, and this risk is particularly
high, with nearly 5-fold increase, among younger males. Potential limitations
include unmeasured risk factors and a referral bias at a tertiary medical
center; larger studies are required to confirm these findings.
Extrahepatic Manifestations
1066. Is
HOMA-IR the best marker of insulin resistance in chronic hepatitis due to HCV
infection?
R. Narita; M. Hiura;
S. Abe; Y. Kihara; A. Tabaru; M. Otsuki.
Background and Aims:
Recent epidemiological studies have suggested that hepatitis
C (HCV) infection is associated with an increased risk of development of type 2
diabetes mellitus (DM). Elucidation of the relationship between chronic HCV
infection (
Methods:
We enrolled a total of 202
Result:
There was a significant correlation between [AUC]0-180 min of glucose or insulin and HOMA-IR. Pearson’s
correlations coefficient (r) and the P values for these correlations were r =
0.334 and 0.562, and P<0.0001 and <0.001 respectively. Matsuda index
[104/√(mean insulin after OGTT x mean glucose
after OGTT x fasting glucose x fasting insulin)] strongly correlated with
HOMA-IR (r = 0.855, P<0.0001). Glucose 0-30[AUC] x insulin 0-30[AUC], which
reflects an index of hepatic resistance to insulin, had a significant but much
weaker correlation with HOMA-IR (r = 0.534, P<0.0001).
Conclusion:
Although HOMA-IR is an useful index
of IR, determination of hepatic insulin resistance using of HOMA-IR is not
feasible in
Disease Progression –
S. Seronello; C. Ito;
T. Wakita; J. Choi.
Introduction:
Hepatitis C virus (HCV) causes severe alteration of the host
redox status, and ethanol is a well-known cofactor in the hepatopathogenesis
induced by HCV. Ethanol metabolism generates reactive oxygen species (
Methods:
In this study, we use JFH1 strain that produces infectious
virus particles in Huh7 cells to demonstrate that ethanol, at subtoxic and
physiologically relevant concentrations, elevates HCV RNA level in the context
of the complete lifecycle of HCV. Ethanol also increases HCV RNA in the
subgenomic JFH1-Luc (genotype 2a) and Con1-Neo (genotype 1b) RNA-transfected
cells, suggesting that the HCV RNA genome replication is affected, independent
of the genotype. Acetaldehyde likewise elevates HCV RNA at physiological
concentrations. In contrast, decreasing intracellular glutathione (
Conclusion:
Therefore, ethanol is likely to enhance HCV replication
through acetaldehyde rather than
Extrahepatic Manifestations
1075.
Hepatitis C virus infection enhances insulin resistance induced by visceral fat
accumulation.
Y. Eguchi; T. Mizuta;
E. Ishibashi; T. Eguchi; A. Matsunobu; N. Oza; S. Nakashita; Y. Kitajima; H.
Takahashi; Y. Kawaguchi; R. Iwakiri; I. Ozaki; N. Ono; K. Fujimoto.
Background:
Recently, an association between hepatitis C virus (HCV)
infection and insulin resistance (IR) has been noted. Although visceral fat
accumulation is closely related to IR in subjects with metabolic syndrome and
nonalcoholic fatty liver disease (NAFLD), the possible effect of HCV on
visceral fat accumulation remains unclear.
Aim:
To evaluate the relationship between IR and visceral fat
accumulation in HCV-infected patients and then compared the incidence of IR
between HCV-infected patients and NAFLD patients with or without visceral fat
accumulation.
Methods:
A total of 87 HCV-infected patients in comparison with 125
sex- and age-matched patients with NAFLD were recruited. In order to exclude a
confounding effect of advanced hepatic fibrosis on IR, the patients were
limited to HCV patients with fibrosis stages 1 and 2 (n=87; 39 males and 48
females) and platelet counts of >15 x 104 /mm3. The patients were included
if they fulfilled the following criteria: absence of diabetes mellitus; absence
of markers of hepatitis B virus; no evidence of autoimmune liver disease or
alcoholic liver disease (>20 g of alcohol per day). We evaluated the degree
of visceral fat area (VFA; cm2) at the umbilical level was measured by computed
tomography and divided into two grades: no visceral obesity, VFA<100;
visceral obesity, VFA≥100. IR was evaluated by homeostasis model
assessment of IR (HOMA-IR) and the quantitative insulin sensitivity check index
(QUICKI). Pancreatic beta-cell function was evaluated by homeostasis model
assessment of beta-cell function (HOMA-beta). Serum soluble TNF-receptors 1 and
2 and adiponectin were measured.
Results:
Body mass index, waist circumference, VFA, total cholesterol,
triglyceride and fasting plasma glucose were significantly higher in NAFLD
patients than in HCV-infected patients, whereas aminotransferase and HOMA-beta
were significantly higher in HCV-infected patients than in NAFLD patients.
HOMA-IR and QUICKI was correlated with visceral fat accumulation, and higher in
HCV patients than in NAFLD patients with visceral obesity. HOMA-beta was higher
in HCV patients than in NAFLD patients for each VFA grade. There was no
difference between the levels of adiponectin in HCV-infected patients and NAFLD
patients with visceral obesity. Serum soluble TNF-receptor 1 and 2 were higher
in HCV patients than in NAFLD patients with visceral obesity.
Conclusions:
These results indicate that HCV infection is a risk factor
for development of IR, particularly in patients with visceral obesity. The
progression of IR may be enhanced by an increase in TNF activity in
HCV-infected patients with visceral obesity.
Extrahepatic Manifestations
1084.
Microsomal triglyceride transfer protein (
É. F. Siqueira; C. P.
Oliveira; M. Corrêa-Giannella; J. Stefano; A. Cavaleiro; M. Z. Fortes; M. C.
Muniz; K. A. Silva; F. S. Silva; L. B. Pereira; F. J. Carrilho.
Background & Aims:
Chronic hepatitis C (
Methods:
Eight six untreated patients with HCV RNA and liver biopsy
proven
Results:
Conclusion:
Our results indicate that the presence of G allele of
Disease Progression – HCC
C. Braconi; F. Meng;
N. Huang; T. Suzuki; C. Taccioli; C. Croce; T. Patel.
Background:
Methods:
HepG2 human
Results:
Compared to controls, HCV-positive Hep-394 cells had a lower
IC50 to sorafenib (1.0 +/- 0.1 vs 3.5+/- 0.8 μΜ) or doxorubicin (0.8
+/- 0.1 vs 1.7 +/- 0.1 μΜ). Compared to controls, HCV positive cells
had significant alterations in expression of selected miRNA, with 10 miRNA
(3.1% of total) > 2-fold down-regulated and 27 miRNA (8.4% of total) >
2-fold up-regulated (p<0.01). Of these, miR-193b and miR-29b were prominently
increased in expression (by 3.6 and 1.8-fold respectively), whereas miR-206 and
miR-627 were decreased (by 5.0 and 3.0-fold respectively) in HCV-positive
Summary and
Conclusions:
Cellular expression of HCV proteins increases sensitivity to
sorafenib by miRNA-dependent modulation of Mcl-1 and cellular apoptosis. We
conclude that enhancing the miRNA responses involved in response to
chemotherapy may be useful for individualized therapy in