HCV-infected Subjects Research Articles

Chronic viral hepatitis in HIV infected patients

Results Of the 826 HIP evaluated during the study period, chronic HBV infection was found in 198 HIP (23.97%), chronic HCV infection in 6 HIP (0.73%). Chronic HBVHDV coinfection was detected in 6 HIP (9.37%, of 64 HIP evaluated) and chronic HBV-HCV coinfection in 2 HIP (0.24%). The evolution of chronic HBV infection during the study period was as follows: HBs seroconversion in 8 HIP (4.04%), chronic hepatitis-167 HIP (84.34%), cirrhosis-17 HIP (8.59%), undefined (lost to follow-up)-6 HIP (3.03%). Complete data necessary for the evaluation of HBV infection phase were available for 27 HIP; according to these data, the distribution of the evaluated subjects was as follows: HBe antigen negative chronic hepatitis B was detected in 8 HIP (29.63%), HBe antigen positive chronic hepatitis B in 6 HIP (22.22%) and immune control phase in 13 HIP (48.15%). 54 deaths (27.27%) were recorded among chronic HBV infected subjects; 18 deaths (9.10%) were liver related. The evolution of chronic HCV infection during the study period was as follows: chronic hepatitis in 3 HIP (50%) and cirrhosis in 3 HIP (50%). 1 death (16.67%) was recorded among chronic HCV infected subjects; this death was liver related.

MicroRNA-122 Abundance in Hepatocellular Carcinoma and Non-Tumor Liver Tissue from Japanese Patients with Persistent HCV versus HBV Infection

Mechanisms of hepatic carcinogenesis in chronic hepatitis B and hepatitis C are incompletely defined but often assumed to be similar and related to immune-mediated inflammation. Despite this, several studies hint at differences in expression of miR-122, a liver-specific microRNA with tumor suppressor properties, in hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) versus hepatitis C virus (HCV) infection. Differences in the expression of miR-122 in these cancers would be of interest, as miR-122 is an essential host factor for HCV but not HBV replication. To determine whether the abundance of miR-122 in cancer tissue is influenced by the nature of the underlying virus infection, we measured miR-122 by qRT-PCR in paired tumor and non-tumor tissues from cohorts of HBV- and HCV-infected Japanese patients. miR-122 abundance was significantly reduced from normal in HBV-associated HCC, but not in liver cancer associated with HCV infection. This difference was independent of the degree of differentiation of the liver cancer. Surprisingly, we also found significant differences in miR-122 expression in non-tumor tissue, with miR-122 abundance reduced from normal in HCV- but not HBV-infected liver. Similar differences were observed in HCV- vs. HBV-infected chimpanzees. Among HCV-infected Japanese subjects, reductions in miR-122 abundance in non-tumor tissue were associated with a single nucleotide polymorphism near the IL28B gene that predicts poor response to interferon-based therapy (TG vs. TT genotype at rs8099917), and correlated negatively with the abundance of multiple interferon-stimulated gene transcripts. Reduced levels of miR-122 in chronic hepatitis C thus appear to be associated with endogenous interferon responses to the virus, while differences in miR-122 expression in HCV- versus HBV-associated HCC likely reflect virus-specific mechanisms contributing to carcinogenesis. The continued expression of miR-122 in HCV-associated HCC may signify an important role for HCV replication late in the progression to malignancy.

Hepatitis C virus itself is a causal risk factor for chronic kidney disease beyond traditional risk factors: a 6-year nationwide cohort study across Taiwan

BackgroundHepatitis C virus (HCV) infection and chronic kidney disease (CKD) have high prevalences in Taiwan and worldwide, but the role of HCV infection in causing CKD remains uncertain. This cohort study aimed to explore this association.MethodsThis nationwide cohort study examined the association of HCV with CKD by analysis of sampled claims data from Taiwan National Health Insurance Research Database from 1998 to 2004. ICD-9 diagnosis codes were used to identify diseases. We extracted data of 3182 subjects who had newly identified HCV infection and no traditional CKD risk factors and data of randomly selected 12728 matched HCV-uninfected control subjects. Each subject was tracked for 6 years from the index date to identify incident CKD cases. Cox proportional hazard regression was used to determine the risk of CKD in the HCV-infected and control groups.ResultsThe mean follow-up durations were 5.88 years and 5.92 years for the HCV-infected and control groups, respectively. Among the sample of 15910 subjects, 251 subjects (1.6%) developed CKD during the 6-year follow-up period, 64 subjects (2.0%) from the HCV-infected group and 187 subjects (1.5%) from the control group. The incidence rate of CKD was significantly higher in the HCV-infected group than in the control group (3.42 vs. 2.48 per 1000 person-years, p = 0.02). Multivariate analysis indicated that the HCV-infected group had significantly greater risk for CKD (adjusted hazard ratio: 1.75, 95% CI: 1.25-2.43, p = 0.0009). This relationship also held for a comparison of HCV-infected and HCV-uninfected subjects who were younger than 70 years and had none of traditional CKD risk factors.ConclusionsHCV infection is associated with increased risk for CKD beyond the well-known traditional CKD risk factors. HCV patients should be informed of their increased risk for development of CKD and should be more closely monitored.

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

In this study, we demonstrate that killer cell lectin-like receptor subfamily G member 1 (KLRG1), a transmembrane protein preferentially expressed on T cells, is highly expressed on CD56(+) NK cells, which are significantly reduced in their numbers and functions in the peripheral blood of patients with chronic hepatitis C virus (HCV) infection compared to subjects without infection. KLRG1 expression is also upregulated on healthy NK cells exposed to Huh-7 hepatocytes infected with HCV in vitro. Importantly, the expression levels of KLRG1 are inversely associated with the capacity of NK cells to proliferate and to produce gamma interferon (IFN-γ) but positively associated with apoptosis of NK cells in response to inflammatory cytokine stimulation. KLRG1(+) NK cells, including CD56(bright) and CD56(dim) subsets, exhibit impaired cell activation and IFN-γ production but increased apoptosis compared to KLRG1(-) NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-γ production by NK cells from HCV-infected subjects. Blockade of KLRG1 also enhanced the impaired phosphorylation of Akt (Ser473) in NK cells from HCV-infected subjects. Taken together, these results indicate that KLRG1 negatively regulates NK cell numbers and functions via the Akt pathway, thus providing a novel marker and therapeutic target for HCV infection.

Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of GSK2336805, an Inhibitor of Hepatitis C Virus (HCV) NS5A, in Healthy Subjects and Subjects Chronically Infected with HCV Genotype 1

GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metabolism, and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, reductions in HCV RNA were observed within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log reduction in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median tmax (time to maximum concentration of drug in serum) of 4.5 versus 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals. (This study has been registered at ClinicalTrials.gov under registration no. NCT01277692.).

Characterization of Hepatitis C Virus Resistance from a Multiple-Dose Clinical Trial of the Novel NS5A Inhibitor GS-5885

GS-5885 is a novel hepatitis C virus (HCV) NS5A inhibitor. In a 3-day monotherapy study in treatment-naive genotype 1a (GT1a) and GT1b HCV-infected subjects, median viral load reductions ranged from 2.3 to 3.3 log10 HCV RNA IU/ml across dosing cohorts (1, 3, 10, 30, or 90 mg once daily). Here, we report viral sequencing and phenotypic analysis of clinical isolates from this study. Detection of baseline NS5A amino acid substitutions at positions 28, 30, 31, or 93 in GT1a was associated with a reduced treatment response. In the GT1b cohort, Y93H was detected in 100% of subjects at day 4 or 14. In the Gt1a cohort, population sequencing detected NS5A resistance-associated mutations at day 4 or 14 for 3/10 subjects at the 1-mg dose and for all subjects dosed at ≥3 mg. A subset of mutants that confer a low level of reduced susceptibility to GS-5885 was not detected by population sequencing at the 30- and 90-mg doses. Subject-derived M28T, Q30R, L31M, and Y93C mutations all conferred >30-fold reductions in GS-5885 and daclatasvir susceptibilities in vitro. Site-directed NS5A mutants also showed reduced susceptibility to GS-5885. However, all NS5A mutants tested remained fully susceptible to other classes of direct-acting antivirals (DAAs), interferon alpha, and ribavirin. Importantly, the nonoverlapping resistance profile and high potency of GS-5885 support its further development with other direct-acting antivirals for the treatment of chronic HCV. (This study has been registered at ClinicalTrials.gov under registration number NCT01193478.).

Psychiatric co-morbidity among subjects with heroin and cocaine use disorders and its association with HCV infection

Aim: This study aims to determine whether psychiatric co-morbidity is associated with HCV infection in a substance misuse population.Methods: We identified all subjects in the National Drug Treatment Monitoring System (NDTMS) during the period January 2007–December 2010 for whom information was recorded which identified their psychiatric co-morbidity status and their HCV status. Multivariate analysis was used to identify risk factors that could predict HCV infection.Results and conclusions: The HCV prevalence rate was 32%. HCV infected subjects were younger (21.4% versus 23.1%) when they first started to use drugs, they were more likely to be white (85.1% versus 13.1%) and male (74% versus 72.6%), to have urgent housing problems (13.0% versus 9.7%), to inject (42.8% versus 18.8%), and to share injecting paraphernalia (35.4% versus 9.2%). After adjusting for demographics and drug and alcohol use behaviours, the Odds Ratio of psychiatric co-morbidity for HCV infection was 1.33 (95% CI 1.01–1.75). The results suggest that psychiatric co-morbidity is associated of HCV infection.Clinical implications: It is important to take psychiatric co-morbidity into account when treating these patients and designing intervention strategies.

Impact of Hepatitis C Virus (HCV) infection on biomolecular markers influencing the pathogenesis of bladder cancer

ObjectiveThe present study was designed to determine the possible impact of hepatitis C virus (HCV) infection on the expression of telomerase (TERT), retinoblastoma (RB1), E2F3, TP53, CDKN1A (p21) and fibroblast growth factor receptor- 3 (FGFR3) genes in patients with bladder cancer (BC).Materials and methods100 patients with bladder cancer (15 female and 85 male) were divided into 2 groups; Group I: 50 HCV negative subjects (age range 36–79), and Group II: 50 HCV positive subjects (age range 42–80). Expressions of the telomerase, retinoblastoma (Rb), E2F3, TP53 and FGFR3 genes were tested by immunohistochemistry and real time PCR in tumour tissues and healthy bladder tissues. Also, telomerase activity was assessed by telomeric repeats amplification protocol (TRAP).ResultsBladder tumors associated with HCV infection were of high grade and invasive squamous cell carcinomas (SCCs). Expressions of hTERT, Rb, E2F3, TP53 and FGFR3 as well as telomerase activity were significantly higher in bladder tissues of HCV-infected patients compared with bladder tissues of non infected patients (p<0.05). On the contrary, CDKN1A (p21) expression was significantly lower in bladder tissues of HCV-infected patients compared to bladder tissues of non infected patients (p<0.05).ConclusionThe expressions of hTERT, Rb, E2F3, TP53 and FGFR3 as well as the activity of telomerase were significantly high in malignant bladder tissues associated with HCV infection. On the other hand, CDKN1A (p21) expression was low in bladder tissues of HCV-infected subjects. Moreover, there was a positive correlation between HCV infection and expression of telomerase, E2F3, TP53 and FGFR3. There was a negative correlation between HCV infection and expression of Rb and p21.

Serum prolactin levels and prolactin mRNA expression in peripheral blood mononuclear cells in hepatitis C virus infection

Prolactin is not only a pituitary hormone but an immunoregulatory hormone secreted from lymphocytes. Prolactin induction in relation to hepatitis C virus (HCV) infection has not been elucidated. The serum levels of prolactin were examined in 232 HCV-infected subjects positive for anti-HCV antibody and 65 healthy controls negative for it, who were recruited in the cohort study. The prolactin mRNAs were measured in peripheral blood mononuclear cells (PBMCs) of eleven healthy volunteers including five men and six women before and after stimulation by HCV in vitro. The serum level of prolactin and prolactin mRNA in PBMCs were measured by chemiluminescence immunoassay and real-time PCR, respectively. The serum levels of prolactin were significantly higher in the HCV-infected subjects (median: 7.5, IQR: 5.7-10.9 ng/ml) than in the controls (median: 5.6, IQR: 4.4-8.3 ng/ml) (P < 0.01). They were significantly higher in HCV-infected males (median: 8.0, IQR: 5.9-11.8 ng/ml) than in the controls (median: 4.8, IQR: 4.2-5.9 ng/ml) (P < 0.001), however, the difference was not significant between HCV-infected females (median: 7.3, IQR: 5.6-10.5 ng/ml) and the controls (median: 6.4, IQR: 5.3-9.8 ng/ml). The mRNA expression of prolactin was induced in PBMCs of all males, but it was induced in PBMCs of the two of six females examined in vitro. These results suggest that the serum level of prolactin is higher in HCV-infected males than in healthy males, and that HCV infection induces the mRNA expression of prolactin in PBMCs that is more apparent in male than in females.

Interferon-α Is the Primary Plasma Type-I IFN in HIV-1 Infection and Correlates with Immune Activation and Disease Markers

Type-I interferon (IFN-I) has been increasingly implicated in HIV-1 pathogenesis. Various studies have shown elevated IFN-I and an IFN-I-induced gene and protein expression signature in HIV-1 infection, yet the elevated IFN-I species has not been conclusively identified, its source remains obscure and its role in driving HIV-1 pathogenesis is controversial. We assessed IFN-I species in plasma by ELISAs and bioassay, and we investigated potential sources of IFN-I in blood and lymph node tissue by qRT-PCR. Furthermore, we measured the effect of therapeutic administration of IFNα in HCV-infected subjects to model the effect of IFNα on chronic immune activation. IFN-I bioactivity was significantly increased in plasma of untreated HIV-1-infected subjects relative to uninfected subjects (p = 0.012), and IFNα was the predominant IFN-I subtype correlating with IFN-I bioactivity (r = 0.658, p<0.001). IFNα was not detectable in plasma of subjects receiving anti-retroviral therapy. Elevated expression of IFNα mRNA was limited to lymph node tissue cells, suggesting that peripheral blood leukocytes are not a major source of IFNα in untreated chronic HIV-1 infection. Plasma IFN-I levels correlated inversely with CD4 T cell count (p = 0.003) and positively with levels of plasma HIV-1 RNA and CD38 expression on CD8 T cells (p = 0.009). In hepatitis C virus-infected subjects, treatment with IFN-I and ribavirin increased expression of CD38 on CD8 T cells (p = 0.003). These studies identify IFNα derived from lymph nodes, rather than blood leukocytes, as a possible source of the IFN-I signature that contributes to immune activation in HIV-1 infection.

Association between hepatitis B or hepatitis C virus infection and risk of pancreatic adenocarcinoma development: A systematic review and meta-analysis

BackgroundPancreatic adenocarcinoma (PAC) is an aggressive cancer with a poor prognosis. To date, PAC causes are still largely unknown. Antigens and replicative sequences of oncogenic hepatitis B (HBV) and hepatitis C (HCV) virus were detected in different extra-hepatic tissues, including pancreas. Objectivea systematic review and meta-analysis of epidemiological studies assessing PAC risk in patients with HBV/HCV chronic infections. MethodsIn September 2012, we extracted the articles published in Medline, Embase and the Cochrane Library, using the following search terms: “chronic HBV” and “HCV”, “hepatitis”, “PAC”, “risk factors”, “epidemiology”. Only case/control (C/C), prospective/retrospective cohort studies (PCS/RCS) written in English were collected. Resultsfour hospital-based C/C studies and one PCS, in HBV-infected patients and two hospital-based C/C studies and one RCS in HCV-infected subjects met inclusion criteria. In these studies HBsAg positivity enhanced significantly PAC risk (RR = 1.18, 95% CI:1.04–1.33), whereas HBeAg positivity (RR = 1.31, 95% CI:0.85–2.02) as well as HBsAg negative/HBcAb positive/HBsAb positive pattern (RR = 1.12, 95% CI:0.78–1.59) and HBsAg negative/HBcAb positive/HBsAb negative pattern (RR = 1.30, 95% CI:0.93–1.84) did not. Relationship between PAC risk and anti-HCV positivity was not significant, although it reached a borderline value (RR = 1.160, 95% CI:0.99–1.3). ConclusionsHBV/HCV infection may represent a risk factor for PAC, but the small number of available researches, involving mainly populations of Asian ethnicity and the substantial variation between different geographical areas in seroprevalence of HBV/HCV-antigens/antibodies and genotypes are limiting factors to present meta-analysis.

Hepatitis C virus and human immunodeficiency virus transmission routes: Differences and similarities

Bouare et al found that hepatitis C virus (HCV) infection in Malian women is mainly transmitted through medical procedures with contaminated supplies, and that human immunodeficiency virus (HIV) transmission is predominantly sexual. The results of this study confirm those of a recent case-control study in New York and Oregon which demonstrated that healthcare exposures represent an important source of new HCV infections in United States. HCV seroprevalence was only 0.2% in pregnant, young Malian women, indicating that hygiene improved in healthcare facilities over time. Heterosexual transmission of HCV is exceptional, and can occur, from males to females, in extremely rare occasions in case of vaginal mucosal damage or less rarely through anal intercourse. The Malian study did not show an association between HIV infection and hospitalization, transfusion, tattoo, dental care. Transmission by needle-stick injury occurs in 0.9%-2.2% of exposures from HCV-infected subjects and in 0.1%-0.3% of exposures from HIV-infected individuals. HCV is therefore more transmissible through percutaneous exposure.

The strange and critical intersection of hepatitis C and lipoprotein metabolism: “C-zing” the oil

Since its discovery in 1989, a substantial amount of research has emerged regarding the close association of hepatitis C virus (HCV) replication and hepatic lipoprotein metabolism. Even before the identification of the HCV virus, a link to fat metabolism was suspected based on clinical observations regarding steatosis as a common feature of what used to be known as “non-A, non-B hepatitis.”1 This relationship was later extended in studies that revealed that HCV-infected patients with steatosis often lack common risk factors for fatty liver, such as obesity.2 These early observations, along with subsequent studies that identified circulating viral particles in low-density, more-buoyant plasma fractions (partitioned with plasma centrifugation in sucrose or iodixanol gradients), fueled a now extensive and growing body of literature on this key aspect of HCV replication.3 Investigations performed over the past 23 years have defined replicative pathways of HCV involving mechanisms and biochemical pathways right out of the “play book” of fatty liver disease (FLD).

Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis

Hepatitis C virus (HCV)-specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV-specific CD8(+) T cells, is a key regulatory cytokine modulating HCV-specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV-specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross-sectional study of two well-defined groups of HCV-infected subjects with slow (≤ 0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV-specific T-cell responses were studied using interferon-gamma (IFNγ)-ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme-linked immunosorbent assay (ELISA) and multiparameter fluorescence-activated cell sorting (FACS). The effects of IHL stimulated with HCV-core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV-specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV-specific IFNγ responses strongly correlated with HCV-specific TGFβ, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV-specific IL-10. HCV-specific TGFβ was produced by CD8 and CD4 T cells. HCV-specific TGFβ, not interleukin (IL)-10, inversely correlated with liver inflammation (R = -0.63, P = 0.008) and, unexpectedly, fibrosis (R = -0.46, P = 0.05). In addition, supernatants from HCV-stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti-TGFβ mAb abrogated such expression. Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV-specific T cells appeared to have a protective role in HCV-infected liver, together with other T-cell-derived factors, ameliorating HCV liver disease progression.

Acetaminophen-induced acute liver injury in HCV transgenic mice

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500mg/kg in fed animals; or 200mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility.

Insulin Sensitivity and Variability in Hepatitis C Virus Infection Using Direct Measurement

Studies investigating insulin resistance (IR) in chronic hepatitis C virus (HCV) infection have used surrogate measures of IR that have limited reliability. We aimed to describe the distribution and risk factors associated with IR and its change over time in HCV using direct measurement. One hundred two non-cirrhotic, non-diabetic, HCV-infected subjects underwent clinical, histologic, and metabolic evaluation, and 27 completed repeat evaluation at 6 months. Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Three subjects with diabetes were excluded and 95 completed all testing. SSPG ranged from 39 to 328 mg/dL (mean 135 mg/dL) and was stable over time (mean SSPG change -0.3 mg/dL). SSPG was associated with Latino ethnicity (Coef 67, 95 % CI 37-96), BMI (Coef 19 per 5 kg/m(2), 95 % CI 5-32), ferritin (Coef 1.4 per 10 ng/ml, 95 % CI 0.2-2.5), male gender (Coef -48, 95 % CI -80 to -16), and HDL (Coef -16, 95 % CI -28 to -5 mg/dL). Current tobacco use (Coef 55, 95 % CI 19-90), steatosis (Coef -44, 95 % CI -86 to -3), and increases in BMI (Coef 30 per 5 kg/m(2), 95 % CI 6-53) and triglyceride (Coef 3.5 per 10 mg/dL, 95 % CI 0.3-6.7) predicted change in SSPG. There was a wide spectrum of insulin resistance in our HCV population. Host factors, rather than viral factors, appeared to more greatly influence insulin action and its change in HCV.

Rapid early innate control of hepatitis C virus during IFN‐α treatment compromises adaptive CD4+T‐cell immunity

The ability to control HCV with IFN-α-based treatments provides an opportunity in humans to study how the rate of viral clearance in vivo impinges on the development of antiviral responses. Ex vivo (IFN-γ-producing) and cultured antiviral CD4+ T cells, serum cytokines, and viral loads were measured repeatedly in a cohort of chronically HCV-infected subjects (n = 33) receiving IFN-α. Rapid control of virus indicated by an increased calculated rate of virus clearance, occurred in those subjects demonstrating absent/minimal T-cell responses (p < 0.0006). Surprisingly, in subjects who demonstrated the most robust T-cell responses (and reduced serum IL-10), there was actually a reduced rate of early virus clearance. A subsequent analysis of NK-cell function in available subjects (n = 8) revealed an inverse correlation between pretreatment NK-cell expression of NKp46 and the potential to upregulate cytotoxic function on exposure to IFN-α (p < 0.004), as well as the subsequent measured rate of viral clearance (p = 0.045). Thus, the CD4+ T-cell response during IFN-α treatment appears to be shaped by the rate of innate virus suppression. These data suggest that individuals who respond most effectively to immune intervention may be most in need of subsequent vaccination to prevent reinfection.

Laser captured hepatocytes show association of butyrylcholinesterase gene loss and fibrosis progression in hepatitis C-infected drug users.

Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with precirrhosis liver fibrosis (Ishak fibrosis 3-5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in precirrhosis fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity was already decreased at study inception in 19 fibrosis progressors compared with 20 fibrosis nonprogressors (P < 0.05). Nonprogressors also had decreased BCHE activity over time compared with initial values, but these evolved a median (range) 8.6 (7.8-11.4) years after the study period inception (P < 0.05). Laser captured portal tracts were enriched for immune related genes when compared with hepatocytes but precirrhosis livers lost this enrichment. Chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.

In Vitro Antigen-Specific Induction of IL-22 in Human Subjects that Resolved HCV Infection

AIMS: To determine if in vitro production of IL-22 and IL-17 correlated with resolution of HCV infection. MATERIALS #ENTITYSTARTX00026; METHODS: Human peripheral blood cells isolated from a well-defined cohort of resolved and chronic HCV-infected subjects were used to measure HCV-, influenza- and mitogen-activated T-cell proliferation. In addition, IL-22 and IL-17 production was measured via ELISAs and flow cytometry. RESULTS: Resolved HCV subjects had a significantly higher T-cell proliferative response to recombinant NS3 protein compared with chronic HCV subjects. Resolved subjects had a dose-dependent IL-22 response to recombinant NS3 compared with chronic HCV subjects. CONCLUSION: IL-22 production is associated with antigen-specific induction of CD4 (+) T cells in individuals that resolved HCV infection, suggesting a potential role for IL-22 in HCV clearance.

Analysis of IL28B variants in an Egyptian population defines the 20 kilobases minimal region involved in spontaneous clearance of hepatitis C virus.

Spontaneous clearance of hepatitis C virus (HCV) occurs in ∼30% of acute infections. Host genetics play a major role in HCV clearance, with a strong effect of single nucleotide polymorphisms (SNPs) of the IL28B gene already found in different populations, mostly infected with viral genotypes 1 and 3. Egypt has the highest prevalence of HCV infection in the world, which is mostly due to viral genotype 4. We investigated the role of several IL28B SNPs in HCV spontaneous clearance in an Egyptian population. We selected nine SNPs within the IL28B genomic region covering the linkage disequilibrium (LD) block known to be associated with HCV clearance in European populations. These SNPs were genotyped in 261 HCV-infected Egyptian subjects (130 with spontaneous clearance and 131 with chronic infection). The most associated SNPs were rs12979860 (P = 1.6×10−7) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6×10−7). Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ∼20 kilobases. HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142.