Caring Ambassadors Program Hepatitis C C

Transcription

Caring Ambassadors Program
Hepatitis C Newsletter
www.HepCChallenge.org
November 2014
CLINICAL TRIALS, COHORT STUDIES, PILOT STUDIES
BASIC AND APPLIED SCIENCE, PRE-CLINICAL STUDIES
HIV/HCV COINFECTION
COMPLEMENTARY AND ALTERNATIVE MEDICINE
EPIDEMIOLOGY, DIAGNOSTICS & MISCELLANEOUS WORKS
LIVER CANCER
1-3
4-4
4-6
6-6
6-14
14-17
CLINICAL TRIALS, COHORT STUDIES, PILOT STUDIES
Pharmacokinetics, safety, and tolerability of faldaprevir in patients with renal impairment.
Huang F1, Moschetti V2, Lang B, et al. Antimicrob Agents Chemother. 2014 Oct 27. pii:
AAC.03359-14. [Epub ahead of print]
Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary
excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg)
in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with
subjects with normal renal function, the adjusted geometric mean ratios (90% confidence interval)
for overall exposure AUC0-∞ were 113.6% (41.6-310.2%), 178.3% (85.2-373.0%), and 169.2%
(73.2-391.2%) for subjects with mild, moderate, or severe renal impairment, respectively. Overall,
5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment
reported adverse events, with gastrointestinal events being the most common. No severe or serious
adverse events or deaths were reported. These results suggest that moderate or severe renal
impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be
related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal
impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients
with renal impairment is not warranted. (ClinicalTrials.gov registration number NCT01957657).
Hepatitis C virus acquisition among Egyptians: analysis of a 10-year surveillance of acute
hepatitis C. Mohsen A1, Bernier A, LeFouler L, et al. Trop Med Int Health. 2014 Oct 22. doi:
10.1111/tmi.12410. [Epub ahead of print]
OBJECTIVE: To identify current risk factors for hepatitis C virus (HCV) acquisition among
Egyptians. METHODS: Patients with acute HCV were identified through a surveillance system of
acute hepatitis in four fever hospitals in Egypt between 2002 and 2012. Case-control analysis was
conducted, cases being incident acute symptomatic HCV and controls being acute hepatitis A
identified at the same hospitals. The questionnaire covered iatrogenic, community and household
exposures to HCV in the 1-6 months prior to onset of symptoms. Multivariate models were built to
identify risk factors associated with HCV acquisition among non-drug users and drug users
separately. RESULTS: Among non-drug users, hospital admission was independently associated
with acute HCV infection (OR = 4.2, 95% CI = 1.7-10.5). Several iatrogenic procedures, for
example admission in a surgery unit, sutures, IV injections and IV infusions, highly correlated with
hospital admission, were also associated with acute HCV infection and could have been used in the
final model instead of hospital admission. Among drug users, identified risk factors were multiple
Caring Ambassadors Program Hepatitis C Literature Review © 2014
sexual relations (OR = 4.0, 95% CI = 1.1-14.7), intravenous drug use (OR = 3.9, 95% CI = 1.213.0) and shaving at the barbershops (OR = 8.7, 95% CI = 2.4-31.4). Illiteracy and marriage were
significant risk factors in both groups. CONCLUSION: Invasive medical procedures are still a
major risk for acquiring new HCV infections in Egypt, as is illicit drug use in spreading HCV
infection.
Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. Antonelli A, Ferrari SM,
Giuggioli D, et al. World J Diabetes. 2014 Oct 15;5(5):586-600. doi: 10.4239/wjd.v5.i5.586.
Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that
cause devastating health and financial burdens worldwide. Diabetes can be classified into two major
types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that
encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many
epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC)
infection. The processes through which CHC is associated with T2DM seem to involve direct viral
effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated
mechanisms. Few data have been reported on the association of CHC and T1DM and reports on
the potential association between T1DM and acute HCV infection are even rarer. A small number
of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain
cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic
CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared
with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported
improvements in glucose metabolism after antiviral treatment. Further studies are needed to
improve prevention policies and to foster adequate and cost-effective programmes for the
surveillance and treatment of diabetic CHC patients.
Concordance of Sustained Virologic Response 4, 12, and 24 Weeks Post-Treatment With
Sofosbuvir-Containing Regimens for Hepatitis C Virus. Yoshida EM1, Sulkowski MS, Gane
EJ, et al. Hepatology. 2014 Oct 14. doi: 10.1002/hep.27366. [Epub ahead of print]
Historically, clinical trials of regimens to treat chronic infection with the hepatitis C virus (HCV)
have used as their primary efficacy endpoint a sustained virologic response (SVR)-defined as HCV
RNA levels below a designated threshold of quantification-24 weeks after the end of treatment
(SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post-treatment
(SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However,
the concordance between SVR12 and SVR24 has not been systematically assessed with new
regimens of recently approved direct-acting antiviral agents. The purpose of this study was to assess
the concordance between SVR at various post-treatment time points in phase 3 clinical trials of
sofosbuvir-containing regimens. We conducted a retrospective analysis of 5 trials enrolling 863
patients infected with HCV genotypes 1-6. The concordance between SVR at 4 weeks posttreatment (SVR4) and SVR12, and between SVR12 and SVR24 were determined, as well as positive
predictive values (PPV) and negative predictive values (NPV). Overall, 779 of 796 patients (98.0%)
with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV
100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of
SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post-therapy, 77.6% did so
within 4 weeks of completing therapy. Conclusion: Data from phase 3 studies demonstrate that
with sofosbuvir-based regimens, with or without interferon, SVR12 and SVR24 correlate closely.
Thus SVR12 can be used effectively to determine "cure" rates in trials and in clinical practice.
(Hepatology 2014;).
Correlates of Adiponectin in Hepatitis C Infected Children: The Importance of Body Mass
Index.Delgado-Borrego A1, Gonzalez-Peralta RP, RoshanRaza, et al. J Pediatr Gastroenterol Nutr.
2014 Oct 13. [Epub ahead of print]
OBJECTIVES:: Adiponectin is a regulator of cytokines that, in turn, play a vital role in
inflammatory and immune responses. Adiponectin is therefore likely to have a contributory role in
hepatitis C virus (HCV) infection. We sought to characterize adiponectin levels and examine
correlates in a pediatric HCV infected cohort. METHODS:: We performed across-sectional study
in children (5-17 years of age, n = 86) in the Pediatric Study of Hepatitis C (Peds-C) trial.
Adiponectin levels were univariately correlated with patient demographics, anthropometrics, viral
and histological measures. Multivariate regression models were used to identify the unique (i.e., nonconfounded) associations with adiponectin concentrations. RESULTS:: Body mass index (BMI)had
the highest univariate inverse correlation with Logeadiponectin(r = - 0.5, p < 0.0001). In multivariate
analysis, BMI remained inversely correlated with Loge adiponectin after accounting for age and
route of HCV transmission (r = - 0.38, p = 0.0003). Steatosis and fibrosis were inversely related to
loge adiponectin in univariate analysis but these associations were not statistically significant after
multivariate adjustments (p's ≥ .1827). CONCLUSION:: High BMI among HCV infected children
is associated with lower adiponectin levels. Practitioners should be cognizant of the possible risks of
low adiponectin when managing HCV infected children who are overweight. Further studies are
indicated to determine the impact of having low adiponectin on HCV infection in youth.
Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus
Infection After Liver Transplantation. Charlton M1, Gane E2, Manns MP3, et al.
Gastroenterology. 2014 Oct 7. pii: S0016-5085(14)01194-9. doi: 10.1053/j.gastro.2014.10.001. [Epub
ahead of print]
BACKGROUND & AIMS: Interferon alfa-based regimens used to treat recurrent hepatitis C virus
(HCV) infection after liver transplantation are poorly tolerated, associated with generally modest
efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an
interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin
for 24 weeks in treating post-transplant HCV infection. METHODS: In a prospective, multicenter,
open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any
genotype after a primary or secondary liver transplant. All patients received 24 weeks of sofosbuvir
400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine
clearance and hemoglobin values. The primary endpoint was sustained virologic response 12 weeks
after treatment (SVR12). RESULTS: Of the 40 patients enrolled and treated, 78% were male, 85%
were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been
previously treated with interferon. SVR12 was achieved by 28/40 patients (70%; 90% confidence
interval, 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable
viral resistance during or after treatment. The most common adverse events were fatigue (30%),
diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two
patients discontinued study treatment because of adverse events, which were considered unrelated to
study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any
concomitant immunosuppressive agents were reported. CONCLUSION: Sofosbuvir and ribavirin
combination therapy for 24 weeks is an effective and well tolerated interferon-free treatment for
post-transplant HCV infection. ClinicalTrials.gov number: NCT01687270.
BASIC AND APPLIED SCIENCE, PRE-CLINICAL STUDIES
Regulation of core expression during the hepatitis C virus life cycle. Afzal MS1, Alsaleh K1,
Farhat R, et al. J Gen Virol. 2014 Oct 28. pii: vir.0.070433-0. doi: 10.1099/vir.0.070433-0. [Epub
ahead of print]
Core plays a critical role during HCV assembly, not only as a structural component of the virion, but
also as a regulator of the formation of assembly sites. In this study, we observed that core is
expressed later than other HCV proteins in a single viral cycle assay, resulting in a relative increase of
core expression during a late step of the viral life cycle. This delayed core expression results from an
increase of core half-life, indicating that core is initially degraded and is stabilized at a late step of the
HCV life cycle. A stabilization-mediated delayed kinetics of core expression was also observed using
heterologous expression systems. Core stabilization did not depend on its interaction with nonstructural proteins or lipid droplets but was correlated to its expression levels and its oligomerization
status. Therefore in the course of a HCV infection, core stabilization likely occurs when the prior
amplification of the viral genome during an initial replication step allows core to be synthesized at
higher levels as a stable protein during the assembly step of the viral life cycle.
Structure-function analysis of hepatitis C virus envelope glycoproteins E1 and E2. Nayak A1,
Pattabiraman N, Fadra N, et al. J Biomol Struct Dyn. 2014 Oct 15:1-13. [Epub ahead of print]
J Biomol Struct Dyn. 2014 Oct 15:1-13. [Epub ahead of print]
Hepatitis C virus (HCV) is the leading cause of chronic liver disease in humans. The envelope
proteins of HCV are potential candidates for vaccine development. The absence of threedimensional (3D) structures for the functional domain of HCV envelope proteins [E1.E2] monomer
complex has hindered overall understanding of the virus infection, and also structure-based drug
design initiatives. In this study, we report a 3D model containing both E1 and E2 proteins of HCV
using the recently published structure of the core domain of HCV E2 and the functional part of E1,
and investigate immunogenic implications of the model. HCV [E1.E2] molecule is modeled by using
aa205-319 of E1 to aa421-716 of E2. Published experimental data were used to further refine the
[E1.E2] model. Based on the model, we predict 77 exposed residues and several antigenic sites
within the [E1.E2] that could serve as vaccine epitopes. This study identifies eight peptides which
have antigenic propensity and have two or more sequentially exposed amino acids and 12 singular
sites are under negative selection pressure that can serve as vaccine or therapeutic targets. Our
special interest is 285FLVGQLFTFSPRRHW299 which has five negatively selected sites (L286,
V287, G288, T292, and G303) with three of them sequential and four amino acids exposed (F285,
L286, T292, and R296). This peptide in the E1 protein maps to dengue envelope vaccine target
identified previously by our group. Our model provides for the first time an overall view of both the
HCV envelope proteins thereby allowing researchers explore structure-based drug design
approaches.
HIV/HCV COINFECTION
Chronic Inflammation in a Long-Term Cohort of HIV-Infected Patients According to the
Normalization of the CD4:CD8 Ratio. Saracino A1, Bruno G, Scudeller L, et al. AIDS Res Hum
Retroviruses. 2014 Oct 31. [Epub ahead of print]
Abstract In HIV-infected patients a low CD4:CD8 ratio can persist despite CD4 recovery with
long-term antiretroviral treatment (ART). As CD4:CD8 inversion is considered a marker of
immune-senescence, we aimed to assess if it was associated with the chronic inflammation state in
aging patients with HIV. A total of 112 patients with a >15 year history of HIV infection and ART
were included, 85 of whom were suppressed. All subjects were tested for interleukin (IL)-6, highsensitivity (hs)-PCR, and D-dimer levels. Complete clinical, therapeutic, and hematochemical data
were retrieved. Coreceptor tropism based on HIV-DNA gp120 genotyping was also available within
the past 6 months. A progressive increase in the CD4:CD8 ratio over time was observed without
reaching a plateau. Based on the CD4:CD8 ratio at the time of testing, patients were classified into
group A (normal ratio ≥0.9) and group B (<0.9). A normal ratio was observed in 37% of patients.
Variables associated with an inverted CD4:CD8 ratio were older age, nadir CD4, and detectable HIV
viremia. No association between HIV subtype, coreceptor tropism, cytomegalovirus (CMV),
hepatitis B virus (HBV), and hepatitis C virus (HCV) coinfections and CD4:CD8 ratio was
observed. Group B patients showed a trend for a higher frequency of diabetes and
hypertriglyceridemia compared to group A patients, but they did not differ in IL-6, hs-PCR, and Ddimer levels or in frequency of severe non-AIDS-associated events. In conclusion, CD4:CD8 ratio
normalization occurs rarely, even after several years of ART. Chronic inflammation in patients aging
with HIV does not seem to be directly dependent on the CD4:CD8 ratio. However, the persistent
immune dysregulation expressed by a CD4:CD8 inversion might be linked to a higher risk of nonAIDS events, especially metabolic disorders
rs7903146 Polymorphism at Transcription Factor 7 Like 2 Gene Is Associated with Total
Cholesterol and Lipoprotein Profile in HIV/Hepatitis C Virus-Coinfected Patients. PinedaTenor D1, Berenguer J, Jiménez-Sousa MA, et al. AIDS Res Hum Retroviruses. 2014 Oct 29. [Epub
ahead of print]
Transcription factor 7 like 2 (TCF7L2) rs7903146 polymorphism has been associated with metabolic
disturbance and cardiovascular disease. The aim of this study was to analyze the association between
TCF7L2 rs7903146 polymorphism and potential disturbances on the lipid profile in human
immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. We performed a crosssectional study on 263 HIV/HVC-coinfected patients. TCF7L2 polymorphism was genotyped by
GoldenGate assay. The analysis was performed by linear and logistic regression under a dominant
model of inheritance. The variables analyzed were total cholesterol (TC), high-density lipoprotein
(HDL-C), low-density lipoprotein (LDL-C), non-HDL-C, and triglycerides. Patients harboring the
rs7903146 TT/TC genotype showed a diminished concentration of TC (p=0.003), LDL-C
(p=0.004), HDL-C (p=0.012), and non-HDL-C (p=0.013), a lower percentage of TC≥200 mg/dl
(p=0.038), and a higher percentage of HDL≤40 mg/dl (p=0.023). In addition, we observed that
rs7903146 was differently related to fasting serum lipid levels according to the HCV-genotype
(HCV-GT). With regard to HCV-GT1 patients, the rs7903146 TT/TC genotype was associated with
lower levels of HDL-C [adjusted arithmetic mean ratio (aAMR)=0.91; p=0.049] and an elevated
percentage of patients with HDL-C≤40 mg/dl [adjusted odds ratio (aOR)=3.26; p=0.003]. For
HCV-GT3 patients, the rs7903146 TT/TC genotype was associated with lower serum values of TC
(aAMR=0.81; p=0.037), LDL-C (aAMR=0.67; p=0.001), and non-HDL-C (aAMR=0.75; p=0.002)
and a reduced percentage of TC≥200 mg/dl (aOR=0.089; p=0.037). In conclusion, the TCF7L2
rs7903146 TT/TC genotype was associated with lower levels of TC, LDL, and HDL in HCV-GT3
patients, and lower levels of HDL-C in HCV-GT1 patients, suggesting a role in cardiovascular
disease and a potential use as a biomarker in HIV/HCV-coinfected patients.
The clinical management of HCV in the HIV-infected patient. Norton B1, Naggie S. Antivir
Ther. 2014 Oct 27. doi: 10.3851/IMP2910. [Epub ahead of print]
Chronic hepatitis C affects an estimated 170 million persons worldwide and due to shared
transmission routes many persons are coinfected with HIV. Since the advent of highly active
antiretroviral therapy, HIV patients have longer life expectancy and are suffering fewer AIDS-related
complications. The result has been an increase in morbidity and mortality from HIV-associated nonCaring Ambassadors Program Hepatitis C Literature Review © 2014
AIDS condition, with high rates of liver related deaths resulting from HCV in the coinfected
population. Coinfection with HIV is an independent predictor of liver disease progression, and
proper staging of fibrosis is of critical importance in the coinfected patient. In contrast to HIV, it is
possible to eradicate HCV infection; and undetectable viral load 12 weeks after cessation of therapy,
or sustained viral response (SVR), is considered a clinical cure. As achievement of SVR has been
associated with significantly reduced mortality from liver disease and liver disease complications, it is
imperative that patients coinfected with HIV/HCV receive therapy for their HCV infection. The
length of therapy with previously available interferon-based regimens added a significant burden to
HIV/HCV co-infected patients. Newer all-oral, interferon-free regimens promise to simplify
treatment regimens, reduce side-effect profiles, and demonstrate reduced drug interactions with
numerous HAART regimens.
Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus
recover genotype cross-reactive neutralising antibodies to HCV during antiretroviral
therapy. Lee S1, Saraswati H2, Yunihastuti E, et al. Clin Immunol. 2014 Oct 8. pii: S15216616(14)00224-1. doi: 10.1016/j.clim.2014.09.013. [Epub ahead of print]
When severely immunodeficient HIV/HCV co-infected patients are treated with antiretroviral
therapy, it is important to know whether HCV-specific antibody responses recover and whether
antibody profiles predict the occurrence of HCV-associated immune restoration disease (IRD). In
50 HIV/HCV co-infected patients, we found that antibody reactivity and titres of neutralising
antibodies (nAb) to JFH-1 (HCV genotype 2a virus) increased over 48weeks of therapy.
Development of HCV IRD was associated with elevated reactivity to JFH-1 before and during the
first 12weeks of therapy. Individual analyses of HCV IRD and non-HCV IRD patients revealed a
lack of an association between nAb responses and HCV viral loads. These results showed that
increased HCV-specific antibody levels during therapy were associated with CD4+ T-cell recovery.
Whilst genotype cross-reactive antibody responses may identify co-infected patients at risk of
developing HCV IRD, neutralising antibodies to JFH-1 were not involved in suppression of HCV
replication during therapy.
COMPLEMENTARY AND ALTERNATIVE MEDICINE
EPIDEMIOLOGY, DIAGNOSTICS, AND MISCELLANEOUS WORKS
Provision of Clinical Pharmacist Services for Individuals With Chronic Hepatitis C Viral
Infection: Joint Opinion of the GI/Liver/Nutrition and Infectious Diseases Practice and
Research Networks of the American College of Clinical Pharmacy. Mohammad RA1, Bulloch
MN, Chan J, et al. Pharmacotherapy. 2014 Oct 31. doi: 10.1002/phar.1512. [Epub ahead of print]
The objective of this opinion paper was to identify and describe potential clinical pharmacists'
services for the prevention and management of patients infected with the hepatitis C virus (HCV).
The goals of this paper are to guide the establishment and development of pharmacy services for
patients infected with HCV and to highlight HCV research and educational opportunities.
Recommendations were based on the following: a review of published data on clinical pharmacist
involvement in the treatment and management of HCV-infected patients; a consensus of clinical
pharmacists who provide direct patient care to HCV-infected patients and practice in different
pharmacy models, including community-based and academic settings; and a review of published
guidelines and literature focusing on the treatment and management of HCV infections. The
recommendations provided in this opinion paper define the areas of clinical pharmacist involvement
and clinical pharmacy practice in the treatment and management of patients with HCV. Clinical
pharmacists can promote preventive measures and education about reducing HCV transmission,
improve medication adherence, assist in monitoring clinical and adverse effects, recommend
treatment strategies to minimize adverse effects and drug interactions, and facilitate medication
acquisition and logistics that positively improve patient outcomes and reduce the health care system
costs.
A system for the continuous directed evolution of proteases rapidly reveals drug-resistance
mutations. Dickinson BC1, Packer MS1, Badran AH, et al. Nat Commun. 2014 Oct 30;5:5352. doi:
10.1038/ncomms6352
The laboratory evolution of protease enzymes has the potential to generate proteases with
therapeutically relevant specificities and to assess the vulnerability of protease inhibitor drug
candidates to the evolution of drug resistance. Here we describe a system for the continuous
directed evolution of proteases using phage-assisted continuous evolution (PACE) that links the
proteolysis of a target peptide to phage propagation through a protease-activated RNA polymerase
(PA-RNAP). We use protease PACE in the presence of danoprevir or asunaprevir, two hepatitis C
virus (HCV) protease inhibitor drug candidates in clinical trials, to continuously evolve HCV
protease variants that exhibit up to 30-fold drug resistance in only 1 to 3 days of PACE. The
predominant mutations evolved during PACE are mutations observed to arise in human patients
treated with danoprevir or asunaprevir, demonstrating that protease PACE can rapidly identify the
vulnerabilities of drug candidates to the evolution of clinically relevant drug resistance.
An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a
Hypervariable Viral Determinant. Nivarthi UK1, Gras S2, Kjer-Nielsen L, et al. J Immunol. 2014
Oct 29. pii: 1401357. [Epub ahead of print]
Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge
on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire
targeted at an immunodominant, but highly mutable, HLA-B*0801-restricted epitope
(1395HSKKKCDEL1403 [HSK]). To investigate if the narrow TCR repertoire facilitates CTL
escape, structural and biophysical studies were undertaken, alongside comprehensive functional
analysis of T cells targeted at the natural variants of HLA-B*0801-HSK in different HCV genotypes
and quasispecies. Interestingly, within the TCR-HLA-B*0801-HSK complex, the TCR contacts all
available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates
cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies,
albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants
comprising these mutations are reportedly rare and transient in nature, presumably due to fitness
costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a
blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings
simultaneously advance the understanding of anti-HCV immunity and indicate the potential for
cross-genotype HCV vaccines.
The continuum of hepatitis C testing and care. Viner K1, Kuncio D, Newbern EC, et al.
Hepatology. 2014 Oct 28. doi: 10.1002/hep.27584. [Epub ahead of print]
A Hepatitis C virus (HCV) infected person will ideally have access to quality health care and move
through the HCV care continuum(CoC) from HCV antibody (Ab) screening, HCV RNA
confirmation, engagement and retention in medical care, and treatment. Unfortunately, studies show
that many patients do not progress through this continuum. Because these studies may not be
generalizable, we assessed the HCV-CoC in Philadelphia from January 2010 to December 2013 at
the population level. The expected HCV seroprevalence in Philadelphia during 2010-2013 was
calculated by applying NHANES prevalences to age-specific census data approximations and
published estimates of homeless and incarcerated populations. HCV laboratory results reported to
the Philadelphia Department of Public Health and enhanced surveillance data were used to
determine where individuals fell on the continuum. The HCV-CoC was defined as follows: Stage 1HCV Ab screening; Stage 2 - HCV Ab and RNA testing; Stage 3 - RNA-confirmation and
continuing care; Stage 4 - RNA-confirmation, care, and HCV treatment. Of approximately 1,584,848
Philadelphia residents, 47,207 (2.9%) were estimated to have HCV. Positive HCV results were
received for 13,596 individuals, of whom 6,383 (47%) had a positive HCV RNA test. Of these,
1,745 (27%) were in care and 956 (15%) had or were currently receiving treatment. Conclusion:
This continuum provides a 'real-life' snapshot of how this disease is being managed in a major US
urban center. Many patients are lost at each stage, highlighting the need to raise awareness among
health care professionals and at-risk populations about appropriate hepatitis testing, referral,
support, and care.
COBAS® AmpliPrep/COBAS® Taqman ® HCV Quantitative Test, Version 2.0: An In Vitro
Test for Hepatitis C Virus RNA Quantification. Deeks ED. Mol Diagn Ther. 2014 Oct 29.
[Epub ahead of print]
The COBAS® AmpliPrep/COBAS® Taqman® HCV Quantitative Test, version 2.0, is an in vitro,
fully automated, real-time, nucleic acid amplification test indicated for quantifying hepatitis C virus
(HCV) RNA levels in the plasma/serum of patients infected with HCV of genotypes 1-6 who are
receiving anti-viral therapy. By quantifying levels of HCV RNA in these patients, the test can be
used early in the course of treatment to predict the likelihood of a sustained virologic response being
achieved and can also be used to assess virologic response during treatment as part of responseguided therapy. The test has excellent sensitivity, high specificity and a broad linear range of
quantitation. It correlates well with version 1.0 of the same test, but has the benefit of better
sensitivity and genotype inclusivity and a smaller sample input volume. It also correlates well with
other available HCV tests, including other quantitative real-time PCR tests (specifically the
COBAS® Taqman® HCV Test, version 2.0, used with the high pure system, and the Abbott
Realtime and Artus HCV QS-RGQ tests), the Versant® branched DNA quantitative test, the
COBAS® Amplicor HCV Qualitative PCR Test and the Versant® HCV qualitative transcriptionmediated amplification assay. The test is not indicated for HCV infection diagnosis or to screen for
the presence of HCV in blood/blood products.
Functional conservation despite structural divergence in ligand-responsive RNA switches.
Boerneke MA1, Dibrov SM1, Gu J, et al. Proc Natl Acad Sci U S A. 2014 Oct 27. pii: 201414678.
An internal ribosome entry site (IRES) initiates protein synthesis in RNA viruses, including the
hepatitis C virus (HCV). We have discovered ligand-responsive conformational switches in viral
IRES elements. Modular RNA motifs of greatly distinct sequence and local secondary structure have
been found to serve as functionally conserved switches involved in viral IRES-driven translation and
may be captured by identical cognate ligands. The RNA motifs described here constitute a new
paradigm for ligand-captured switches that differ from metabolite-sensing riboswitches with regard
to their small size, as well as the intrinsic stability and structural definition of the constitutive
conformational states. These viral RNA modules represent the simplest form of ligand-responsive
mechanical switches in nucleic acids.
Persistent HCV infection impairs ribavirin antiviral activity through clathrin-mediated
trafficking of equilibrative nucleoside transporter 1. Panigrahi R1, Chandra PK1, Ferraris P1, et
al. J Virol. 2014 Oct 22. pii: JVI.02492-14. [Epub ahead of print]
Ribavirin (RBV) continues to be an important component of interferon-free hepatitis C treatment
regimens, as RBV alone does not inhibit HCV replication effectively; the reason for this
ineffectiveness has not been established. In this study, we investigated the RBV resistance
mechanism using a persistently infected HCV cell culture system. The antiviral activity of RBV
against HCV was progressively impaired in the persistently infected culture, whereas interferon
lambda (IFN-λ1), a Type III IFN, showed a strong antiviral response and induced viral clearance.
We found that HCV replication in persistently infected cultures induces an autophagy response that
impairs RBV uptake by preventing the expression of equilibrative nucleoside transporter 1 (ENT1).
The Huh-7.5 cell line treated with an autophagy inducer, Torin 1, down-regulated membrane
expression of ENT1 and terminated RBV uptake. In contrast, autophagy inhibitors
hydroxychloroquine (HCQ), 3-Methyladenine (3-MA), and Bafilomycin A1 (BafA1) prevented
ENT1 degradation and enhanced RBV antiviral activity. The HCV-induced autophagy response, as
well as treatment with Torin 1, degrades clathrin heavy chain expression in a hepatoma cell line.
Reduced expression of the clathrin heavy chain by HCV prevents ENT1 recycling to the plasma
membrane and forces the ENT1 to the lysosome for degradation. This study provides a potential
mechanism for the impairment of RBV antiviral activity in persistently infected HCV cell cultures,
and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy for
improving RBV antiviral activity against HCV infection. IMPORTANCE: The results from this
work will allow a review of the competing theories of antiviral therapy development in the field of
HCV virology. Ribavirin (RBV) remains an important component of interferon free hepatitis C
treatment regimens. The reason why RBV alone does not inhibit HCV replication effectively has not
been established. This study provides a potential mechanism why RBV antiviral activity is impaired
in persistently infected HCV cell culture, and suggests that inhibition of the HCV-induced
autophagy response could be used as a strategy to increase RBV antiviral activity against HCV
infection. Therefore, it is anticipated that this work would generate a great deal of interest, not only
among Virologists, but also among the general public.
A View of the E2-CD81 Interface at the Binding Site of a Neutralizing Antibody against
Hepatitis C Virus. Harman C1, Zhong L1, Ma L, et al. J Virol. 2014 Oct 22. pii: JVI.01661-14.
Hepatitis C virus (HCV) glycoprotein E2 is considered a major target for generating neutralizing
antibodies against HCV, primarily due to its role of engaging host entry factors such as CD81, a key
cell surface protein associated with HCV entry. Based on a series of biochemical analyses, in
combination with molecular docking, we present a description of a potential binding interface
formed between the E2 protein and CD81. The virus side of this interface includes a hydrophobic
helix motif comprised of residues W437LAGLF442, which encompasses the binding site of a
neutralizing monoclonal antibody, mAb41. The helical conformation of this motif provides a
structural framework for the positioning of residues, F442 and Y443, serving as contact points for
the interaction with CD81. The cell side of this interface likewise involves a surface-exposed
hydrophobic helix, namely the D-helix of CD81, which coincides with the binding site of 1D6, a
monoclonal anti-CD81 antibody known to block HCV entry. Our illustration of this virus-host
interface suggests an important role played by the W437LAGLF442 helix of the E2 protein in the
hydrophobic interaction with the D-helix of CD81, thereby facilitating our understanding of the
mechanism for the antibody-mediated neutralization of HCV. IMPORTANCE: Characterization
of the interface established between the virus and host cells can provide important information
towards the control of virus infections. The interface formed that enables hepatitis C virus (HCV) to
infect human liver cells has not been well-understood because of the number of cell surface
proteins, factors and conditions found to be associated with the infection process. Based on a series
of biochemical analyses, in combination with molecular docking, we present such an interface,
consisting of two hydrophobic helical structures from the HCV E2 surface glycoprotein and the
CD81 protein, a major host cell receptor recognized by all HCV strains. Our study reveals the
critical role played by the hydrophobic interactions in the formation of this virus-host interface,
thereby contributing to our understanding of the mechanism for the antibody-mediated
neutralization of HCV.
Sofosbuvir-based treatment regimens for chronic, genotype 1 hepatitis C virus infection in
u.s. Incarcerated populations: a cost-effectiveness analysis. Liu S, Watcha D, Holodniy M, et
al. Ann Intern Med. 2014 Oct 21;161(8):546-53. doi: 10.7326/M14-0602.
BACKGROUND: Prevalence of chronic hepatitis C virus (HCV) infection is high among
incarcerated persons in the United States. New, short-duration, high-efficacy therapies may expand
treatment eligibility in this population. OBJECTIVE: To assess the cost-effectiveness of sofosbuvir
for HCV treatment in incarcerated populations. DESIGN: Markov model. DATA SOURCES:
Published literature and expert opinion. TARGET POPULATION: Treatment-naive men with
chronic, genotype 1 HCV monoinfection. TIME HORIZON: Lifetime. PERSPECTIVE:
Societal. INTERVENTION: No treatment, 2-drug therapy (pegylated interferon and ribavirin), or
3-drug therapy with either boceprevir or sofosbuvir. For inmates with short remaining sentences
(<1.5 years), only no treatment or sofosbuvir 3-drug therapy was feasible; for those with long
sentences (≥1.5 years; mean, 10 years), all strategies were considered. After release, eligible persons
could receive sofosbuvir 3-drug therapy. OUTCOME MEASURES: Discounted costs (in 2013
U.S. dollars), discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness
ratios. RESULTS OF BASE-CASE ANALYSIS: The strategies yielded 13.12, 13.57, 14.43, and
15.18 QALYs, respectively, for persons with long sentences. Sofosbuvir produced the largest
absolute reductions in decompensated cirrhosis (16%) and hepatocellular carcinoma (9%), resulting
in 2.1 additional QALYs at an added cost exceeding $54 000 compared with no treatment. For
persons with short sentences, sofosbuvir cost $25 700 per QALY gained compared with no
treatment; for those with long sentences, it dominated other treatments, costing $28 800 per QALY
gained compared with no treatment. RESULTS OF SENSITIVITY ANALYSIS: High
reinfection rates in prison attenuated cost-effectiveness for persons with long sentences.
LIMITATIONS: Data on sofosbuvir's long-term effectiveness and price are limited. The analysis
did not consider women, Hispanic persons, or patients co-infected with HIV or hepatitis B virus.
CONCLUSION: Sofosbuvir-based treatment is cost-effective for incarcerated persons, but
affordability is an important consideration.
Coding algorithms for identifying patients with cirrhosis and hepatitis B or C virus using
administrative data. Niu B1, Forde KA, Goldberg DS. Pharmacoepidemiol Drug Saf. 2014 Oct
21. doi: 10.1002/pds.3721. [Epub ahead of print]
BACKGROUND AND AIMS: Despite the use of administrative data to perform epidemiological
and cost-effectiveness research on patients with hepatitis B or C virus (HBV, HCV), there are no
data outside of the Veterans Health Administration validating whether International Classification of
Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes can accurately identify cirrhotic
patients with HBV or HCV. The validation of such algorithms is necessary for future
epidemiological studies. METHODS: We evaluated the positive predictive value (PPV) of ICD-9CM codes for identifying chronic HBV or HCV among cirrhotic patients within the University of
Pennsylvania Health System, a large network that includes a tertiary care referral center, a
community-based hospital, and multiple outpatient practices across southeastern Pennsylvania and
southern New Jersey. We reviewed a random sample of 200 cirrhotic patients with ICD-9-CM codes
for HCV and 150 cirrhotic patients with ICD-9-CM codes for HBV. RESULTS: The PPV of 1
inpatient or 2 outpatient HCV codes was 88.0% (168/191, 95% CI: 82.5-92.2%), while the PPV of 1
inpatient or 2 outpatient HBV codes was 81.3% (113/139, 95% CI: 73.8-87.4%). Several variations
of the primary coding algorithm were evaluated to determine if different combinations of inpatient
and/or outpatient ICD-9-CM codes could increase the PPV of the coding algorithm.
CONCLUSIONS: ICD-9-CM codes can identify chronic HBV or HCV in cirrhotic patients with a
high PPV and can be used in future epidemiologic studies to examine disease burden and the proper
allocation of resources.
Hepatitis C Diagnostics: Clinical Evaluation of the HCV-Core Antigen Determination. van
Helden J1, Weiskirchen R2. Z Gastroenterol. 2014 Oct;52(10):1164-70. doi: 10.1055/s-00341366618. Epub 2014 Oct 14.
BACKGROUND: The aim of the evaluation was to investigate the relevance of the HCV-core
antigen testing for the diagnosis and monitoring of HCV infections in the daily routine. Up to now,
most of the serological diagnostics was performed as determination of antibodies while the
determination of activity and the monitoring of antiviral therapy were checked by HCV RNA PCR.
METHODS: The routine requests for HCV-core antigen of a private laboratory were analyzed for
a period of two years. RESULTS: The determination of HCV antigen highly correlates with the
quantitative measurement of HCV RNA (r = 0.73), p = 0.0003). The diagnostic window is
comparable with that of the HCV PCR (27.1 ± 12.8 d vs. 23.9 ± 9.2 d, p = 0.11). The sensitivity of the
HCV antigen assay was 99.0 % with a specificity of 99.2 %. 54.3 % of the confirmed antibody
positive samples were also antigen positive. Only in 3 of 560 HCV-RNA positive samples HCV
antigen was not detectable, but 3 samples without HCV antibodies were confirmed positive for
HCV antigen. CONCLUSIONS: The HCV antigen assay is a suitable tool for the detection of
chronic active HCV infections, for the early diagnosis of acute infections and for testing of HCV in
patient with immunodeficiency. The HCV antigen assay valuable completion of serological testing
for HCV.
The characteristics of rare codon clusters in the genome and proteins of hepatitis C virus; a
bioinformatics look. Fattahi M1, Malekpour A1, Mortazavi M, et al. Middle East J Dig Dis. 2014
Oct;6(4):214-27.
BACKGROUND Recent studies suggest that rare codon clusters are functionally important for
protein activity. METHODS Here, for the first time we analyzed and reported rare codon clusters
in Hepatitis C Virus (HCV) genome and then identified the location of these rare codon clusters in
the structure of HCV protein. This analysis was performed using the Sherlocc program that detects
statistically relevant conserved rare codon clusters. RESULTS By this program, we identified the
rare codon cluster in three regions of HCV genome; NS2, NS3, and NS5A coding sequence of HCV
genome. For further understanding of the role of these rare codon clusters, we studied the location
of these rare codon clusters and critical residues in the structure of NS2, NS3 and NS5A proteins.
We identified some critical residues near or within rare codon clusters. It should be mentioned that
characteristics of these critical residues such as location and situation of side chains are important in
assurance of the HCV life cycle. CONCLUSION The characteristics of these residues and their
relative status showed that these rare codon clusters play an important role in proper folding of
these proteins. Thus, it is likely that these rare codon clusters may have an important role in the
function of HCV proteins. This information is helpful in development of new avenues for vaccine
and treatment protocols.
Relative effects of heavy alcohol use and Hepatitis C in decompensated chronic liver disease
in a hospital inpatient population. Mankal PK1, Abed J, Aristy JD, et al. Am J Drug Alcohol
Abuse. 2014 Oct 16:1-6. [Epub ahead of print]
Background: Heavy alcohol use has been hypothesized to accelerate disease progression to endstage liver disease in patients with hepatitis C virus (HCV) infection. In this study, we estimated the
relative influences of heavy alcohol use and HCV in decompensated chronic liver disease (CLD).
Methods: Retrospectively, 904 patients with cirrhotic disease admitted to our hospitals during
January 2010-December 2012 were identified based on ICD9 codes. A thorough chart review
captured information on demographics, viral hepatitis status, alcohol use and progression of liver
disease (i.e. decompensation). Decompensation was defined as the presence of ascites due to portal
hypertension, bleeding esophageal varices, hepatic encephalopathy or hepatorenal syndrome. Heavy
alcohol use was defined as a chart entry of greater than six daily units of alcohol or its equivalent.
Results: 347 patients were included based on our selection criteria of documented heavy alcohol use
(n = 215; 62.0%), hepatitis titers (HCV: n = 182; 52.5%) and radiological evidence of CLD with or
without decompensation (decompensation: n = 225; 64.8%). Independent of HCV infection, heavy
alcohol use significantly increased the risk of decompensation (OR = 1.75, 95% CI 1.11-2.75,
p < 0.02) relative to no heavy alcohol use. No significance was seen with age, sex, race, HIV, viral
hepatitis and moderate alcohol use for risk for decompensation. Additionally, dose-relationship
regression analysis revealed that heavy, but not moderate alcohol use, resulted in a three-fold
increase (p = 0.013) in the risk of decompensation relative to abstinence. Conclusions: While both
heavy alcohol use and HCV infection are associated with risk of developing CLD, our data suggest
that heavy, but not moderate, alcohol consumption is associated with a greater risk for hepatic
decompensation in patients with cirrhosis than does HCV infection.
Screening, Diagnosis, Treatment, and Management of Hepatitis C: A Novel,
Comprehensive, Online Resource Center for Primary Care Providers and Specialists.
Lebovics E1, Czobor K2. Am J Med. 2014 Oct 9. pii: S0002-9343(14)00888-2. doi:
10.1016/j.amjmed.2014.10.004. [Epub ahead of print]
Current initiatives focusing on hepatitis C (HCV) screening and diagnosis, together with the advent
of oral interferon (IFN)-free treatment regimens have prompted Elsevier Multimedia Publishing and
the American Journal of Medicine (AJM) to develop a novel, comprehensive, online Resource
Center dedicated to providing both primary care providers and specialists with the latest information
on the screening, diagnosis, treatment, and management of HCV. To date, only 25% of infected
patients have been diagnosed and only 5% cured. With the Centers for Disease Control and
Prevention (CDC) and the US Prevention Services Task Force (USPSTF) recommendation of onetime screening for all individuals born between 1945 and 1965, and the availability of safe and
effective therapy, it is anticipated that primary care providers and community practices will become
increasingly responsible for the screening, diagnosis, and management of infected patients, as well as
providing access to care by specialists when needed. The AJM Hepatitis C Resource Center site will
have two major channels; one channel tailored to specifically address the needs of internal medicine
physicians and other primary care providers, and one channel tailored to address the needs of
specialists including hepatologists, gastroenterologists, and infectious disease specialists. Systematic
surveys of these clinician audiences are being conducted by Elsevier to assess educational gaps, and
ensure that the content of each channel of the Resource Center satisfies the needs of the intended
audiences. In a recent Elsevier survey of primary care physicians (PCPs) who had screened and/or
participated in the care of patients with HCV within 6 months of participating in the survey, 60% of
PCPs stated that they were not very confident or only somewhat confident about screening patients
for chronic HCV infection. A recent Elsevier survey of specialists revealed low levels of satisfaction
with the treatment options available in 2013, with "no therapy" being selected for up to 38% of
patients. This survey also showed that experience with newly-approved options for HCV including
IFN-free regimens is currently limited, but the likelihood that a variety of patient types will be
treated with these options is high. This provides an impetus for educational opportunities focusing
on optimizing treatments for the different HCV genotypes and for patients with comorbidities.
Further results of the PCP and specialist surveys will be published on the Resource Center. Each
channel of the Resource Center will be comprised of a variety of specific communication elements,
which are open to sponsorship, and include roundtable panel discussions, case studies, and direct
links to relevant original research, review articles, and guidelines. All Resource Center components
are peer-reviewed for publication on the Resource Center by the AJM Editorial Office and the
Resource Center Guest Editor, Edward Lebovics, MD. The AJM Hepatitis C Resource Center will
be accessible from the AJM online home page (http://www.amjmed.com) and will be launched
immediately prior to the American Association for the Study of Liver Diseases (AASLD) Liver
Meeting to be held from November 7 to 11, 2014 in Boston, Massachusetts.
Mass Balance, Metabolite Profile and in vitro-in vivo Comparison of Clearance Pathways of
Deleobuvir, a Hepatitis C Polymerase Inhibitor. Chen LZ1, Sabo JP1, Philip E, et al.
Antimicrob Agents Chemother. 2014 Oct 13. pii: AAC.03861-14. [Epub ahead of print]
The pharmacokinetics, mass-balance and metabolism of deleobuvir, an HCV polymerase inhibitor,
were assessed in healthy subjects following a single oral dose of 800 mg of [14C]-deleobuvir (100
μCi). The overall recovery of radioactivity was 95.2%, with 95.1% recovered from feces. Deleobuvir
had moderate to high clearance and the half-life of deleobuvir and radioactivity in plasma was ∼3 h,
indicating that there were no metabolites with half-lives significantly longer than the parent. The
most frequently reported adverse events (6 of 12 subjects) were gastrointestinal disorders. Two
major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene
reduction metabolite formed in the GI tract by gut bacteria (CD 6168), representing ∼20% and 15%
of total drug related material, respectively. Deleobuvir and CD 6168 were the main components in
feces, each representing ∼30 to 35% of the dose. The majority of the remaining radioactivity found
in feces (∼21% of the dose) was accounted for by three metabolites in which deleobuvir underwent
both alkene reduction and monohydroxylation. In fresh human hepatocytes that form biliary
canaliculi in sandwich cultures, the biliary excretion for these excretory metabolites was markedly
higher than deleobuvir and CD 6168, implying that rapid biliary elimination upon hepatic formation
may underlie the absence of these metabolites in circulation. The low in vitro clearance was not
predictive of the observed in vivo clearance, likely because major deleobuvir biotransformation was
by non-CYP450 mediated enzymes that are not well represented in hepatocyte-based in vitro
models.
Cost-effectiveness of rapid HCV testing and simultaneous rapid HCV and HIV testing in
substance abuse treatment programs. Schackman BR1, Leff JA, Barter DM, et al. Addiction.
2014 Oct 8. doi: 10.1111/add.12754. [Epub ahead of print]
AIMS: To evaluate the cost-effectiveness of rapid hepatitis C virus (HCV) and simultaneous
HCV/HIV antibody testing in substance abuse treatment programs. DESIGN: We used a decision
analytic model to compare the cost-effectiveness of no HCV testing referral or offer, off-site HCV
testing referral, on-site rapid HCV testing offer, and on-site rapid HCV and HIV testing offer. Base
case inputs included 11% undetected chronic HCV, 0.4% undetected HIV, 35% HCV co-infection
among HIV-infected, 53% linked to HCV care after testing antibody positive, and 67% linked to
HIV care. Disease outcomes were estimated from established computer simulation models of HCV
(HEP-CE) and HIV (CEPAC). SETTING AND PARTICIPANTS: Data on test acceptance and
costs were from a national randomized trial of HIV testing strategies conducted at 12 substance
abuse treatment programs in the USA. MEASUREMENTS: Lifetime costs (2011 US dollars) and
quality-adjusted life years (QALYs) discounted at 3% annually; incremental cost-effectiveness ratios
(ICERs) FINDINGS: On-site rapid HCV testing had an ICER of $18,300/QALY compared with
no testing, and was more efficient than (dominated) off-site HCV testing referral. On-site rapid
HCV and HIV testing had an ICER of $64,500/QALY compared with on-site rapid HCV testing
alone. In one and two-way sensitivity analyses, the ICER of on-site rapid HCV and HIV testing
remained <$100,000/QALY, except when undetected HIV prevalence was <0.1% or when we
assumed frequent HIV testing elsewhere. The ICER remained <$100,000/QALY in approximately
90% of probabilistic sensitivity analyses. CONCLUSIONS: On-site rapid hepatitis C virus and
HIV testing in substance abuse treatment programs is cost-effective at a <$100,000/ qualityadjusted life years threshold.
Vitamin D pathway gene variants and HCV-2/3 therapy outcomes. Cusato J1, Allegra S,
Boglione L, et al. Antivir Ther. 2014 Oct 3. doi: 10.3851/IMP2853. [Epub ahead of print]
BACKGROUND: The combination of ribavirin and pegylated-interferon-α is considered the
standard of care for HCV-2/3 genotypes treatment. The immune system plays a key role in the
achievement of the sustained virological response (SVR). Vitamin D seems to influence antiviral
response in chronic hepatitis C and its pathway is controlled by polymorphic genes as CYP27B1,
CYP24A1 and VDR. In this study, we have investigated the correlation among the treatment
outcomes and single nucleotide polymorphisms (SNPs) in the above mentioned genes and IL28B
ones. METHODS: One hundred and twelve HCV-2/3 patients treated with interferon plus
ribavirin were retrospectively studied; allelic discrimination was performed by real-time PCR.
RESULTS: CYP24A1rs2585428, IL28Brs12979860 and rs8099917 SNPs affected the non response
and BMI, Metavir score, IL28Brs8099917TT and CYP24A1rs2585428GG were the only factors able
to predict it. SVR was predicted by Metavir score, HCV-RNA at baseline and early virological
response (EVR). IL28Brs12979860 SNP and HCV-RNA were also related to rapid virological
response (RVR). EVR was predicted by BMI, Metavir score and CYP24A1rs2585428 SNP.
IL28Brs8099917TT and FokITT were relapse prediction factors. CONCLUSIONS: As well as to
non genetic factors, SNPs in vitamin D pathway seem to have a role in HCV-2/3 therapy outcomes.
This study reveals the likely usefulness of pharmacogenetic-based ribavirin and interferon therapy to
help identify patients for whom therapy could be successful or not, also considering the new future
expensive therapy options. To date, no similar data were published on these viral genotypes, but
further studies in different and bigger cohorts are needed.
LIVER CANCER
Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding
protein predict the development of hepatocellular carcinoma in hepatitis C patients.
Yamasaki K1, Tateyama M, Abiru S, et al. Hepatology. 2014 Nov;60(5):1563-70. doi:
10.1002/hep.27305. Epub 2014 Oct 2
The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+) -M2BP) was
recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration.
We evaluated the ability of WFA(+) -M2BP to predict the development of hepatocellular carcinoma
(HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who
had been admitted to our hospital with chronic HCV infection without other potential risk factors
were evaluated to determine the ability of WFA(+) -M2BP to predict the development of HCC;
factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine
aminotransferase levels, bilirubin, albumin, platelet count, alpha-fetoprotein (AFP), WFA(+) -M2BP,
and the response to interferon (IFN) therapy. Serum WFA(+) -M2BP levels were significantly
increased according to the progression of liver fibrosis stage (P < 0.001). In each distinctive stage of
fibrosis (F0-F1, F2, F3, and F4), the risk of development of HCC was increased according to the
elevation of WFA(+) -M2BP. Multivariate analysis identified age >57 years, F4, AFP >20 ng/mL,
WFA(+) -M2BP ≥4, and WFA(+) -M2BP 1-4 as well as the response to IFN (no therapy vs.
sustained virological response) as independent risk factors for the development of HCC. The timedependent areas under the receiver operating characteristic curve demonstrated that the WFA(+) M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP.
Chronic HCV infection and lymphoproliferative disorders: mixed cryoglobulinemia
syndrome, MGUS and B-cell non-Hodgkin lymphoma. Caviglia GP1, Sciacca C, Abate ML, et
al. J Gastroenterol Hepatol. 2014 Oct 28. doi: 10.1111/jgh.12837. [Epub ahead of print]
BACKGROUND AND AIM: Chronic hepatitis C (CHC) has been associated with
lymphoproliferaitive disorders (LPD) such as mixed cryoglobulinemia syndrome (MCS), monoclonal
gammopathy of undetermined significance (MGUS) and B-cell non-Hodgkin lymphoma (B-NHL).
The aim of the present study is to assess MCS, MGUS and B-NHL prevalence in a cohort of CHC
infected patients and to evaluate the association of demographic, clinical and virologic factors with
the presence of LPDs. METHODS: A total of 121 CHC patients with LPDs (50M, 71F; mean age
61.5 ± 11.8) and 130 CHC patients without extra-hepatic manifestations (60M, 70F; mean age 60.4
± 9.2) were retrospectively enrolled from a cohort of 1313 CHC patients between January 2006 and
December 2013. Patients with LPDs included: 25 patients with MCS (9M, 16F; mean age 60.2 ±
1.4), 55 patients with MGUS (18M, 37F; mean age 61.3 ± 12.1) and 41 patients with B-NHL (23M,
18F; mean age 62.5 ± 11.0) RESULTS: Patients with MCS (25/1313; 1.9%), MGUS (55/1313;
4.2%) and B-LNH (41/1313; 3.1%) did not differ in age, severity of liver disease, HCV genotype
and response to antiviral therapy. Using multivariate logistic regression analysis, a positive
association was found between the presence of cirrhosis and MGUS (OR=2.8924, 95%CI 1.26936.5909; p=0.012) and between cirrhosis and B-NHL (OR=3.9407, 95%CI 1.7226-9.0153; p=0.001),
while no association with MCS diagnosis emerged. CONCLUSIONS: Despite the pathogenetic
mechanism of HCV-associated LPDs is still unclear, cirrhosis is an additional risk factor for the
development of lymphoproliferative disorders in patients with chronic HCV infection.
Co-expression analysis of differentially expressed genes in hepatitis C virus-induced
hepatocellular carcinoma. Song Q, Zhao C, Ou S, et al. Mol Med Rep. 2014 Oct 17. doi:
10.3892/mmr.2014.2695. [Epub ahead of print]
The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C
virus (HCV)‑induced hepatocellular carcinoma (HCC) using the expression profiles of HCVinfected Huh7 cells at different time points. The differentially expressed genes (DEGs) were
identified with the Samr package in R software once the data were normalized. Functional and
pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in
Cytoscape software was applied to conduct module analysis of the constructed co-expression
networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at
12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling
pathways and biological processes, including sterol biosynthetic processes and tRNA aminoacylation. There were 22 time series genes which were clustered into 3 expression patterns, and the
demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered
into was 24 h post-infection. tRNA synthesis‑related biological processes emerged at 24 and 48 h.
Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h postinfection. In view of this, the screened time series genes have the potential to become candidate
target molecules for monitoring, diagnosing and treating HCV-induced HCC.
Changes in characteristics of hepatitis C patients seen in a liver centre in the United States
during the last decade. Talaat N1, Yapali S, Fontana RJ, et al. J Viral Hepat. 2014 Oct 14. doi:
10.1111/jvh.12343. [Epub ahead of print]
With the approval of 2 direct-acting antivirals (DAAs) in 2011 and anticipation of interferon (IFN)free regimens, more hepatitis C virus (HCV) chronically infected patients are now seeking treatment.
To describe the characteristics of newly referred HCV patients in 2011-2012 (Era-2) and compare
them to those seen in 1998-1999 (Era-1). Retrospective data were collected from HCV patients
newly referred to our tertiary liver clinics. Advanced liver disease was defined as cirrhosis (based on
histology or Aspartate aminotransferase-platelet-ratio index (APRI) >2), hepatic decompensation or
hepatocellular carcinoma (HCC). A total of 1348 patients (538 in Era-1, 810 in Era-2) were included.
Compared to Era-1, Era-2 patients were older (median age 56 vs 45 years), more likely to be black
(17.2% vs 11.6%) and had a longer interval between diagnosis and referral (median 4 vs 2 years).
Genotype (GT) 1 predominated in both Eras with a significant increase in GT1a from 39.9% in Era1 to 53.8% in Era-2. A higher per cent of patients in Era-2 were treatment experienced, but 77%
had never received treatment. Era-2 patients were more likely to have advanced disease at referral
(61.6% vs 51.5%, P < 0.001), with an eightfold higher prevalence of HCC (21.6% vs 2.6%, P <
0.001). HCV patients newly referred in recent years were older, predominantly infected with GT1a
and had more advanced liver disease yet only a quarter had received HCV treatment. Reduction in
HCV disease burden will require development of treatment regimens targeted towards patients in
the current Era as well as increase in diagnosis and referral of patients for treatment.
Neuropathies in hepatitis C-related liver cirrhosis. Abdelkader NA1, Zaky DZ, Afifi H, et al.
Indian J Gastroenterol. 2014 Oct 12. [Epub ahead of print]
INTRODUCTION: Neurological complications occur in a large number of patients with chronic
hepatitis C virus (HCV) infection and range from peripheral neuropathy to cognitive impairment.
We studied the association between neuropathy and HCV-related chronic liver disease. METHOD:
Fifty patients with HCV-related chronic liver disease were enrolled in this prospective case-control
study. Patients were classified into two groups: mild and severe corresponding to a model for endstage liver disease (MELD) score <14 and a MELD score >14, respectively. Complete neurological
examination and nerve conduction studies have been done for all patients. All patients in addition to
25 healthy control subjects were tested for their serum B12 levels. RESULTS: Twenty-two percent
of patients had sensory abnormality, 18 % had motor abnormality, while 10 % had both sensory and
motor abnormalities. Autonomic function tests and nerve conduction studies revealed that 23
patients (46 %) had evidence of neuropathy and 10 patients (20 %) had both peripheral and
autonomic neuropathy. Neuropathies were not related to the severity of the liver disease. Serum B12
level had a very wide range among patients with no relation between its level and neuropathy.
Vitamin B12 level was significantly and directly correlated to MELD score and age.
CONCLUSION: Peripheral and autonomic neuropathy has high prevalence in patients with HCVrelated chronic liver disease. On the other hand, vitamin B12 level is high in those patients and there
is no role for vitamin B12 in the liver cirrhosis-related neuropathy.
Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular
carcinoma: a retrospective analysis of a single North American center. Franssen B1,
Alshebeeb K, Tabrizian P, et al. Ann Surg. 2014 Oct;260(4):650-6; discussion 656-8. doi:
10.1097/SLA.0000000000000917
OBJECTIVE: Compare surgical outcomes for hepatitis B virus (HBV)-hepatocellular carcinoma
(HCC) versus hepatitis C virus (HCV)-hepatocellular carcinoma (HCC). BACKGROUND:
HCC is the second leading cause of death from cancer worldwide and is associated with hepatitis
virus infection in 80% of cases. METHODS: Between 1997 and 2011, 1008 patients with hepatitis
B (HBV, n = 431) or hepatitis C (HCV, n = 577) underwent resection (n = 567) or transplantation
(n = 441). Resection was indicated for Child's A patients with single HCC; transplantation was
indicated for patients within Milan criteria. Univariate and multivariate analyses were performed as
well as survival and recurrence analysis using log-rank test. RESULTS: Based on uniform
application of these criteria, resection: transplantation ratio was 3.6 for patients with HBV and 0.67
for patients with HCV. Resection: Patients with HBV had larger tumors and higher α-fetoprotein
but less satellites and macrovascular invasion; 68% of HBV versus 89% of HCV were cirrhotic.
Survival was better (P < 0.001) and recurrence was lower (P = 0.009) for HBV. Independent
predictors of death included HCV (P = 0.024), transfusion (P = 0.013), and HCC of greater than 5
cm (P = 0.013). Limiting analysis to patients with cirrhosis, survival with HBV remained superior (P
= 0.020) but recurrence did not. Transplantation: Tumors were similar in HBV and HCV. Survival
was better (P = 0.002) for HBV; recurrence was similar. Independent predictors of death were HCV
(P < 0.001), poor differentiation (P = 0.049), vascular invasion (P = 0.002), and outside Milan (P =
0.032). Limiting analysis to patients within Milan, HBV survival remained better for both resection
(P = 0.030) and transplantation (P = 0.002). CONCLUSIONS: Survival after both resection and
transplantation for HCC was better in HBV- than in HCV-related HCC whereas recurrence was also
lower for HBV-HCC in the resection group, these differences are influenced by both liver and
tumor factors.

Caring Ambassadors Program Hepatitis C C

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