Hepatitis C Virus Progression Research Articles

Modelling the impact of improving screening and treatment of chronic hepatitis C virus infection on future hepatocellular carcinoma rates and liver-related mortality.

BackgroundThe societal, clinical and economic burden imposed by the complications of chronic hepatitis C virus (HCV) infection - including cirrhosis and hepatocellular carcinoma (HCC) - is expected to increase over the coming decades. However, new therapies may improve sustained virological response (SVR) rates and shorten treatment duration. This study aimed to estimate the future burden of HCV-related disease in England if current management strategies remain the same and the impact of increasing diagnosis and treatment of HCV as new therapies become available.MethodsA previously published model was adapted for England using published literature and government reports, and validated through an iterative process of three meetings of HCV experts. The impact of increasing diagnosis and treatment of HCV as new therapies become available was modelled and compared to the base-case scenario of continuing current management strategies. To assess the ‘best case’ clinical benefit of new therapies, the number of patients treated was increased by a total of 115% by 2018.ResultsIn the base-case scenario, total viraemic (HCV RNA-positive) cases of HCV in England will decrease from 144,000 in 2013 to 76,300 in 2030. However, due to the slow progression of chronic HCV, the number of individuals with cirrhosis, decompensated cirrhosis and HCC will continue to increase over this period. The model suggests that the ‘best case’ substantially reduces HCV-related hepatic disease and HCV-related liver mortality by 2020 compared to the base-case scenario. The number of HCV-related HCC cases would decrease 50% by 2020 and the number progressing from infection to decompensated cirrhosis would decline by 65%. Therefore, compared to projections of current practices, increasing treatment numbers by 115% by 2018 would reduce HCV-related mortality by 50% by 2020.ConclusionsThis analysis suggests that with current treatment practices the number of patients developing HCV-related cirrhosis, decompensated cirrhosis and HCC will increase substantially, with HCV-related liver deaths likely to double by 2030. However, increasing diagnosis and treatment rates could optimise the reduction in the burden of disease produced by the new therapies, potentially halving HCV-related liver mortality and HCV-related HCC by 2020.

Hepatitis C virus reinfection after liver transplantation: is there a role for direct antiviral agents?

Recurrence of hepatitis C virus (HCV) infection following liver transplantation (LT) is almost universal and can accelerate graft cirrhosis in up to 30% of patients. The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge, considering the shortage of donor organs and the accelerated progression of HCV in LT recipients. Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients, even though the combination is not as effective as it is in immunocompetent patients. A sustained virological response in the setting of LT improves patient and graft survival, but this is only achieved in 30%-45% of patients and the treatment is poorly tolerated. To improve the efficacy of pre- and post-transplant antiviral therapy, a new class of potent direct-acting antiviral agents (DAAs) has been developed. The aim of this review is to summarize the use of DAAs in LT HCV patients. PubMed, Cochrane Library, MEDLINE, EMBASE, Web of Science and clinical trial databases were searched for this purpose. To date, only three clinical studies on the topic have been published and most of the available data are in abstract form. Although a moderately successful early virological response has been reported, DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness. Moreover, the ongoing nature of data, the lack of randomized studies, the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable. In conclusion, large well-designed clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.

De novo autoimmune hepatitis after interferon treatment in a liver transplant recipient with common variable immunodeficiency

A 23-year-old female underwent cadaveric liver transplant (LT) for hepatitis C virus (HCV) genotype 1b cirrhosis. The infection was acquired following infusions of contaminated intravenous gammaglobulins that she had been receiving regularly since she was diagnosed of a common variable immunodeficiency (CVID) when she was 15 years of age. The native liver did not show overlapping features of autoimmune hepatitis (AIH). Initial immunosuppression included tacrolimus, azathioprine and prednisone but, due to neurotoxicity, tacrolimus was converted to cyclosporine after the first month. Azathioprine and prednisone were progressively tapered and discontinued 5 and 4 months post-transplant, respectively. At this time the patient presented with increased transaminase levels (Fig. 1) and the viral load was 4.67 × 106 UI/ml. Tests for autoantibodies, including anti-nuclear, anti-mitochondrial, anti-smooth-muscle, anti-liver-kidney microsomal and anti-liver cytosol antibodies were negative. A first biopsy showed signs of chronic active hepatitis C with a Knodell's index of 1-3-4-1:9. When antiviral therapy was commenced with interferon (IFN) α-2b (3 MU 3 times/week) and ribavirin (RBV) (800 mg/day) she was on monotherapy with cyclosporine (50–100 mg/12 h). She had a good response but complete remission of the virus was not achieved (0.6 × 106 UI/ml). Despite of that, the clinicians maintained the treatment but reduced the dose of IFNα-2b to 1.5 MU to avoid rapid progression of HCV which is frequent in patients with CVID. Twenty-two months after LT, another flare in serum aminotransferases developed and the initial dose of 3 MU was restored. Two months later, a new biopsy showed features of chronic active hepatitis with bridging fibrosis, absence of plasma cells in the infiltrates and a Knodell's index of 4-3-4-3:14. A new rise in liver enzymes 34 months after LT, together with the presence of anti-LC1 antibodies, IgG kappa monoclonal gammopathy (3450 mg/dl) and new findings in biopsy, led to the diagnosis of de novo autoimmune hepatitis (AIH). The liver biopsy revealed chronic active hepatitis with bridging fibrosis, important presence of plasma cells in the inflammatory infiltrate (>10%), hepatocyte rosette formation and a Knodell's index of 4-3-4-3:14. Simultaneously, HCV RNA became undetectable. Viral clearance at the time of diagnosis of de novo AIH suggested a temporal relationship between these two events. IFNα-2b +RBV treatment was discontinued and therapy with prednisone (30 mg/day) was started with very good response including progressive normalization of transaminases, reduction of gammaglobulins and complete disappearance of IgG kappa monoclonal gammopathy. This form of de novo AIH, occurring in patients after IFN treatment for HCV recurrence, was described for the first time in 2006 [ 1 Cholongitas E. Samonakis D. Patch D. et al. Induction of autoimmune hepatitis by pegylated interferon in a liver transplant patient with recurrent hepatitis C virus. Transplantation. 2006; 81: 488-490 Crossref PubMed Scopus (45) Google Scholar , 2 Kontorinis N. Agarwal K. Elhajj N. et al. Pegylated interferon-induced immune-mediated hepatitis post-liver transplantation. Liver Transpl. 2006; 12: 827-830 Crossref PubMed Scopus (58) Google Scholar ]. Eleven years after the diagnosis, the patient continues asymptomatic, with normal transaminase levels and IgG values between 600 and 1000 mg/dl. HCV-RNA continues being negative and serum samples are negative for AIH-associated antibodies. Actual treatment consists of cyclosporine (levels around 80 ng/ml) and prednisone (5–7.5 mg/day).

Metabolomics and proteomics approaches to characterize and assess proteins of bear bile powder for hepatitis C virus

Metabolomics represents an emerging and powerful discipline that provides an accurate and dynamic picture of the phenotype of bio-systems through the study of potential metabolites that could be used as therapeutic targets and for the discovery of new drugs. Hepatitis C virus (HCV) is a leading cause of liver disease worldwide, and is a major burden on public health. It is hypothesized that an animal model of HCV infection would produce unique patterns of endogenous metabolites. Herein, a method for the construction of efficient networks is presented with regard to the proteins of bear bile powder (PBBP) that protect against HCV as a case study. Ultra-performance liquid chromatography, coupled with electrospray ionization/quadrupole-time-of-flight high definition mass spectrometry (UPLC-HDMS), coupled with pattern recognition methods and computational systems analysis were integrated to obtain comprehensive metabolomic profiling and pathways of the large biological data sets. Among the regulated pathways, 38 biomarkers were identified and two unique metabolic pathways were indicated to be differentially affected in HCV animals. The results provided a systematic view of the development and progression of HCV, and also could be used to analyze the therapeutic effects of PBBP, a widely used anti-HCV medicine. The results also showed that PBBP could provide satisfactory effects on HCV infection through partially regulating the perturbed pathway. The most promising use in the near future would be to clarify the pathways for the drugs and obtain biomarkers for these pathways to help guide testable predictions, provide insights into drug action mechanisms, and enable an increase in research productivity toward metabolomic drug discovery.

154-P: ASSOCIATION OF HLA CLASS I AND II WITH HEPATITIS C VIRUS INFECTION IN HIGH-RISK HEMODIALYSIS PATIENTS AWAITING KIDNEY TRANSPLANTATION

Recent evidences have shown that several host genetic factors influence susceptibility or protection to hepatitis C virus (HCV) infection. There are controversial data regarding the associations of human leukocyte antigens (HLA) and clearance or progression of HCV. The aim of this study was to investigate whether particular HLA molecules were associated with HCV infection in recipients awaiting kidney transplantation, considered at high-risk to infection due to protracted hemodialysis treatment. This case-control study included 1404 of 3000 total chronic kidney diseases patients on dialysis, in waiting list for transplantation, enrolled at the Laboratory of Transplantation Immunology of Second University of Naples, Italy. Particularly, we consecutively considered 301 patients with HCV infection and we randomly selected 1103 HCV-negative as control group. None of the patients carried hepatitis B surface antigen or had human immunodeficiency virus antibody to exclude additional viral factors that could affect our results. All patients were tested for HCV antibody detection by serological Chemiluminescent Microparticle Immunoassay (CMIA, Abbott, Italy). All kidney recipients were tested for HLA class I (HLA-A and -B) and class II (-DR) antigens by serological and molecular HLA typing. In our case-control study, HLA-A26 is positively associated with HCV infection, while HLA-A29, -B40 and -DR1 are negatively associated with HCV infection. Multiple logistic regression analysis demonstrated that age (OR=1.02; 95% CI=1.01-1.04; p < 0.00), HLA-A26, -A29, -B40 and -DR1 [(OR=1.54; 95% CI=1.03-2.30; p=0.03); (OR=0.50; 95% CI=0.26-0.99 p=0.05); (OR=0.42; 95% CI=0.23-0,7 p=0.01); (OR=0.62; 95% CI=0.41-0,94 p=0.03); respectively] are independent predictors of HCV infection. Our results suggest that particular HLA molecules, as host genetic factors, may have a relationship with susceptibility or protection to HCV infection also in recipients awaiting kidney transplantation.

Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2

Copy number variants visible with the light microscope have been described as euchromatic variants (EVs) and EVs with extra G-light material at 8q21.2 have been reported only once before. We report four further patients with EVs of 8q21.2 ascertained for clinical (3) or reproductive reasons (1). Enhanced signal strength from two overlapping bacterial artificial chromosomes (BACs) and microarray analysis mapped the EV to a 284-kb interval in the reference genome. This interval consists of a sequence gap flanked by segmental duplications that contain the 12-kb components of one of the largest Variable Number Tandem Repeat arrays in the human genome. Using digital NanoString technology with a custom probe for the RNA exonuclease 1 homologue (S. cerevisiae)-like 1 (REXO1L1) gene within each 12-kb repeat, significantly enhanced diploid copy numbers of 270 and 265 were found in an EV family and a median diploid copy number of 166 copies in 216 controls. These 8q21.2 EVs are not thought to have clinical consequences as the phenotypes of the probands were inconsistent, those referred for reproductive reasons were otherwise phenotypically normal and the REXO1L1 gene has no known disease association. This EV was found in 4/3078 (1 in 770) consecutive referrals for chromosome analysis and needs to be distinguished from pathogenic imbalances of medial 8q. The REXO1L1 gene product is a marker of hepatitis C virus (HCV) infection and a possible association between REXO1L1 copy number and susceptibility to HCV infection, progression or response to treatment has not yet been excluded.

Cost-Effectiveness Analysis of Triple Therapy with Protease Inhibitors in Treatment-Naive Hepatitis C Patients

Chronic hepatitis C is the leading cause of chronic liver disease, representing a significant burden in terms of morbidity, mortality and costs. A new scenario of therapy for hepatitis C virus (HCV) genotype 1 infection is being established with the approval of two effective HCV protease inhibitors (PIs) in combination with the standard of care (SOC), peginterferon and ribavirin. Our objective was to estimate the cost effectiveness of combination therapy with new PIs (boceprevir and telaprevir) plus peginterferon and ribavirin versus SOC in treatment-naive patients with HCV genotype 1 according to data obtained from clinical trials (CTs). A Markov model simulating chronic HCV progression was used to estimate disease treatment costs and effects over patients' lifetimes, in the Spanish national public healthcare system. The target population was treatment-naive patients with chronic HCV genotype 1, demographic characteristics for whom were obtained from the published pivotal CTs SPRINT and ADVANCE. Three options were analysed for each PI based on results from the two CTs: universal triple therapy, interleukin (IL)-28B-guided therapy and dual therapy with peginterferon and ribavirin. A univariate sensitivity analysis was performed to evaluate the uncertainty of certain parameters: age at start of treatment, transition probabilities, drug costs, CT efficacy results and a higher hazard ratio for all-cause mortality for patients with chronic HCV. Probabilistic sensitivity analyses were also carried out. Incremental cost-effectiveness ratios (ICERs) of €2012 per quality-adjusted life-year (QALY) gained were used as outcome measures. According to the base-case analysis, using dual therapy as the comparator, the alternative IL28B-guided therapy presents a more favorable ICER (€18,079/QALY for boceprevir and €25,914/QALY for telaprevir) than the universal triple therapy option (€27,594/QALY for boceprevir and €33,751/QALY for telaprevir), with an ICER clearly below the efficiency threshold for medical interventions in the Spanish setting. Sensitivity analysis showed that age at the beginning of treatment was an important factor that influenced the ICER. A potential reduction in PI costs would also clearly improve the ICER, and transition probabilities influenced the results, but to a lesser extent. Probabilistic sensitivity analyses showed that 95 % of the simulations presented an ICER below €40,000/QALY. Post hoc estimations of sustained virological responses of the IL28B-guided therapeutic option represented a limitation of the study. The therapeutic options analysed for the base-case cohort can be considered cost-effective interventions for the Spanish healthcare framework. Sensitivity analysis estimated an acceptability threshold of the IL28B-guided strategy of patients younger than 60 years.

Association between human leukocyte antigen class I and II alleles and hepatitis C virus infection in high-risk hemodialysis patients awaiting kidney transplantation

Recent evidences have shown that several host genetic factors influence susceptibility or protection to hepatitis C virus (HCV) infection. There are controversial data regarding the associations of human leukocyte antigens (HLA) and the clearance or progression of HCV. The aim of this study was to investigate whether particular HLA molecules were associated with HCV infection in recipients awaiting kidney transplantation considered at high-risk to infection due to protracted hemodialysis treatment. To this purpose, 301 kidney recipients with HCV infection and 1103 uninfected recipients were examined for HLA class I and II molecules. In our case-control study, HLA-A*26 is positively associated with HCV infection while HLA-A*29, -B*40 and -DRB1*01 are negatively associated with HCV infection. Multiple logistic regression analysis demonstrated that age (OR=1.02; 95% CI=1.01–1.04; p<0.00), HLA-A*26, -A*29, -B*40 and -DRB1*01 [(OR=1.54; 95% CI=1.03–2.30; p=0.03); (OR=0.50; 95% CI=0.26–0.99; p=0.05); (OR=0.42; 95% CI=0.23-0, 7; p=0.01); (OR=0.62; 95% CI=0.41-0, 94; p=0.03); respectively] are independent predictors of HCV infection. Our results suggest that particular HLA molecules, as host genetic factors, may have a relationship with susceptibility or protection to HCV infection also in recipients awaiting kidney transplantation.

Distinct microRNA profiles are associated with the severity of hepatitis C virus recurrence and acute cellular rejection after liver transplantation

Recurrent hepatitis C virus (HCV) infection is associated with accelerated fibrosis rates after liver transplantation (LT) and is the leading cause of graft failure. Furthermore, distinguishing recurrent HCV from acute cellular rejection (ACR) can be problematic, and this can lead to inappropriate treatments and adverse outcomes. We hypothesized that intragraft microRNA (miRNA) expression profiles could distinguish the severity of recurrent HCV and differentiate recurrent HCV from ACR. We established meticulously matched post-LT patient cohorts in order to derive robust global miRNA expression profiles and minimize the impact of variables known to influence HCV recurrence. These cohorts consisted of patients with slow HCV fibrosis progression (Ishak stage < F2), fast HCV fibrosis progression (Ishak stage ≥ F2), ACR, and nonviral etiologies. We found increased intragraft expression of miRNA-146a, miRNA-19a, miRNA-20a, and miRNA-let7e in slow progressors versus fast progressors, and we validated these findings with quantitative PCR. This miRNA network regulates the expression of cardinal genes implicated in promoting antifibrogenic, antiangiogenic, and anti-inflammatory pathways. miRNA-19a and miRNA-20a were also specifically detected in the serum of slow progressors. Furthermore, intragraft miRNA expression distinguished fast HCV progression from ACR. Here, changes in the expression of key miRNAs regulating fibrogenic and angiogenic pathways were associated with fast HCV progression. We demonstrate specific miRNA expression signatures that discriminate the rates of fibrosis progression in patients with recurrent HCV, and we distinguish recurrent HCV from ACR after LT. A pathway analysis indicates that specific miRNAs may play a regulatory role in these processes. Selected miRNAs may serve as intragraft and serum biomarkers for recurrent HCV after LT and help to distinguish between ACR and recurrent HCV.

Role of CCR5Δ32 mutation in protecting patients with Schistosoma mansoni infection against hepatitis C viral infection or progression.

Schistosomiasis has been incriminated in the significant increase in hepatitis C virus (HCV) infections, although the association has not been adequately explained. We hypothesized that the CCR5Δ32 mutation may be involved in the high prevalence of HCV with schistosomiasis. The aim was to explore the association between the CCR5Δ32 mutation in schistosomiasis patients and protection against HCV infection or progression. We compared 220 schistosomiasis patients (S group) and 190 patients with HCV and schistosomiasis (HCV/S group) for the presence of the CCR5Δ32 mutation. Clinical, biochemical, and radiological assessments were done. HCV infection was diagnosed with anti-HCV antibodies and a recombinant HCV antigen-based rapid immunochromatographic test, and confirmed by HCV reverse transcriptase PCR. HCV genotyping was done by reverse hybridization line probe assay. Schistosomiasis was diagnosed by FAST-ELISA and indirect hemagglutination for Schistosoma mansoni antibodies, and stool analysis for ova. Polymorphisms of the CCR5 receptor gene were assessed by PCR-based genotyping of the 32-bp deletion at the CCR5 locus in whole blood. Of HCV/S patients, 91.6 vs. 91.8 % of S patients had CCR5 WT/WT homozygosity (nonmutants). Heterozygous and homozygous CCR5Δ32 mutation patterns (CCR5Δ32/WT and CCR5Δ32/Δ32) were distributed similarly in the HCV/S and S groups (6.8 vs. 7.2 % and 0.53 vs. 0.90 %, respectively; p > 0.05, OR = 0.97). Genotype 4 was the predominant viral genotype (93 % of cases). No differences were observed in CCR5 gene patterns according to viral genotype, viral RNA count, or ALT level. However, CCR5Δ32 mutants (homozygous and heterozygous) had a lower rate of severe hepatic fibrosis vs. nonmutants (27 vs. 42 %, p = 0.101, OR = 0.51). Moreover, 53.4 % of CCR5Δ32/WT mutants showed spontaneous viral clearance vs. 26.2 % of nonmutants (p = 0.000, OR = 4.1). In conclusion, no association was detected between the CCR5Δ32 mutation and HCV disease susceptibility in schistosomiasis patients. However, patients with the CCR5Δ32 mutation and HCV infection were less prone to severe hepatic fibrosis and more likely to have spontaneous viral clearance than patients with the nonmutant genotype.

Antiviral peptide nanocomplexes as a potential therapeutic modality for HIV/HCV co-infection

It is estimated that 4 to 5 million people are currently co-infected with Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). HIV/HCV co-infection is associated with unique health risks including increased hepatotoxicity of antiretrovirals, accelerated progression of HCV and liver diseases. The standard interferon-based therapy is effective only in about 50% of patients and often is associated with autoimmune and neuro-psychiatric complications. The treatment of co-infection (HIV/HCV) requires new strategic approaches. To this end, the formulations of an amphiphatic α-helical peptide, a positively charged analog of C5A peptide derived from the HCV NS5A protein, with a reported virocidal activity were prepared by electrostatic coupling with anionic poly(amino acid)-based block copolymers. The self-assembled antiviral peptide nanocomplexes (APN) were ca. 35 nm in size, stable at physiological pH and ionic strength, and retained in vitro antiviral activity against HCV and HIV. Moreover, incorporation of the peptide into APN attenuated its cytotoxicity associated with the positive charge. In vivo APN were able to decrease the viral load in mice transplanted with human lymphocytes and HIV-1-infected. Overall, these findings indicate the potential of these formulations for stabilization and delivery of antiviral peptides while maintaining their functional activity.

Direct Antiviral Agents for the Treatment of Hcv Reinfection after Liver Transplantation

Recurrence of hepatitis C virus (HCV) infection after liver transplantation (LT) is almost universal and leads to cirrhosis in up to 30% of patients by five years. Considering the increasing shortage of donor organs and the accelerated progression of HCV in transplant recipients, the development of effective strategies to treat or prevent HCV recurrence are of paramount importance. Therapy with pegylated–interferon plus ribavirin, although less efficacious than in immunocompetent patients, is currently the treatment of choice of LT recipients with histologically proven recurrence of hepatitis C. However, this combination therapy results in a sustained virological response in around 30-45% of patients and is poorly tolerated. The new classes of potent and direct-acting antiviral agents (DAAs) will certainly improve the results of pre- and post-transplant antiviral therapy. The aim of this review is to identify and summarize the experience with the use of direct-acting antivirals in LT HCV patients. PubMed, the Cochrane Library, MEDLINE, EMBASE and Web of Science databases were searched for this purpose. To date, there are no published clinical studies on this topic and the only available data are in abstract form. The heterogeneous study designs and populations, the small number of enrolled patients, the different treatment schedules and follow-up periods and the ongoing nature of the reports make the results largely inconclusive or even anecdotal. In conclusion, the use of DAAs in HCV liver transplanted patients cannot be recommended until well designed large clinical studies will be performed.

Strategies to reduce hepatitis C virus recurrence after liver transplantation.

Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.

Temporal changes and regional differences in treatment uptake of hepatitis C therapy in EuroSIDA

AbstractUp to 30% of European HIV‐positive patients tested for hepatitis C virus (HCV) are seropositive. All co‐infected patients with chronic HCV and ≥F2 fibrosis should be considered for HCV therapy given their increased risk of death from liver disease. Despite this the extent to which co‐infected patients initiate HCV treatment is not well described. The aims of this study were to determine the rate of HCV treatment uptake among co‐infected patients and to estimate the effect of treatment on all‐cause and liver‐related death. EuroSIDA patients positive for HCV antibody and HCV‐RNA were included in the study. Baseline was defined as the date of recruitment or HCV seroconversion, whichever occurred later. Poisson regression was used to identify temporal changes and regional differences in HCV treatment uptake (use of at least interferon‐α [peg‐IFN]± ribavirin) and to study the association between HCV treatment and progression to all‐cause and liver‐related death. 1947 patients were included, with a median follow‐up time of 107 months (IQR: 57–156). Overall 456 (23.4%) of HIV/HCV co‐infected patients have received HCV therapy so far. The incidence of HCV treatment rose from 0.29 (95% CI: 0.13–0.45) per 100 person‐years follow‐up in 1998 to 5.26 (95% CI: 3.87–65) in 2007, before falling to 3.73 (95% CI: 2.40–5.06) in 2009. There were considerable regional differences (Figure). In a multivariable model treatment incidence increased 11.0% (95% CI: 4.0–18.4; p=0.0016) per 2 calendar years. Patients with CD4 cell counts greater than 350 cell/mm3 (incidence rate ratio [IRR]: 1.75 [1.37–2.23; p &lt; 0.0001]), HIV‐RNA less than 500 copies/ml (IRR: 1.58 [1.18–2.12; p=0.0023]), with HCV genotype 3 (IRR: 1.55 [1.21–1.98; p=0.0006]) compared to genotype 1) and those from south (IRR: 1.99 (1.45–2.72; p&lt;0.0001) and east central Europe (IRR: 1.61 [1.11–2.34; p=0.011]) compared to west Europe, were more likely to initiate treatment. In a multivariable model treatment for HCV was not significantly associated with all‐cause death (355 deaths, IRR: 0.81 [95% CI: 0.54–1.19; p=0.28]) or liver‐related death (95 deaths, IRR: 1.0 [95% CI: 0.50–2.02; p=0.99]). The incidence of treatment for HCV among co‐infected patients increased from 1998 until 2007 and was common in those with higher CD4 cell counts and lower HIV‐RNA, consistent with HCV treatment guidelines. HCV treatment was not associated with all‐cause or liver‐related death in this population. image

Informed deferral: A moral requirement for entry into the hepatitis C virus treatment warehouse

Informed deferral: A moral requirement for entry into the hepatitis C virus treatment warehouse

Oxidative stress pattern in hepatitis C patients co-infected with schistosomiasis

This study was designed to investigate the role of hepatitis C virus (HCV)-induced oxidative stress in the pathogenesis of the disease with the measurement of tumor necrosis factor (TNF-) and super oxide dismutase (SOD). Eighty patients from Hepatology Unit, Faculty of Medicine, Ain Shams University, were investigated. Thirty patients with bilharzial HCV and 30 patients with non-bilharzial HCV as compared to 20 healthy controls of the same age and sex ratio were investigated. The concentrations of liver enzymes [glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), alkaline phosphatase (ALP)], bilirubin (Bil), albumin (Alb) and total protein (TP) as well as TNF-α and Mn-SOD were determined. The mean level of the different liver function tests in the three groups in the study showed that the levels of GOT, GPT and ALP were significantly higher in the HCV groups as compared to the control group (p 0.05). Furthermore, the mean level of TNF-α was significantly higher in the HCV groups as compared to the control group (p < 0.001) and SOD was significantly decreased in the HCV groups as compared to the control group (p < 0.001). There is a cause-effect relationship between increased levels of TNF-α and decreased levels of SOD, relative to progression of chronic HCV, especially with bilharzias co-infection. Supporting the view that oxidative damage plays a role in chronic HCV infection, also TNF-α establishes a positive auto regulatory loop that can amplify the inflammatory response and lead to chronic inflammation. More evidence indicates that HCV block apoptosis and prolong survival of the host cell in order to gain time for replication and increase viral progeny production.

The adverse pharmacology of calcineurin inhibitors and their impact on hepatitis C recurrence after liver transplantation: implications for clinical practice

Calcineurin inhibitors are widely used as maintenance immunosuppressants in solid-organ transplantation to minimize the risk of allograft rejection. Although the use of these agents has transformed the outcomes for patient and graft survival, this has come at a cost, notably the well-known adverse events of nephrotoxicity and metabolic abnormalities, to name a few. Over the last decade, tremendous interest has also focused on the impact of these medications on the replication of hepatitis C virus (HCV), with cyclosporine in particular having a negative effect on viral replication in vitro. Although small retrospective studies suggested that there may be a beneficial effect with cyclosporine on the progression of recurrent HCV and response to interferon, these findings have not been validated in several well-designed randomized controlled trial studies. The authors will review the pharmacology and pharmacokinetics of these well-known drugs and discuss the impact of these medications on the natural history of HCV recurrence after liver transplantation.

Predicted Effects of Treatment for HCV Infection Vary Among European Countries

The dynamics of hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, vary among European countries. It is important to determine the magnitude of the effects of such differences on incidence and mortality of infection. We compared the dynamics of infection and screening and treatment practices among Belgium, France, Germany, Italy, Spain, and the United Kingdom. We also assessed the effects of treatment with pegylated interferon and additional effects of triple therapy with protease inhibitors. We created a country-specific Markov model of HCV progression based on published epidemiologic data (on HCV prevalence, screening, genotype, alcohol consumption among patients, and treatments) and reports of competitive and hepatocellular carcinoma mortality for the 6 countries. The model was used to predict the incidence of HCV-related cirrhosis and its mortality until 2021 for each country. From 2002 to 2011, antiviral therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4% overall. Reductions in incidence and mortality values ranged from 4.0% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. From 2012 to 2021, antiviral treatment of patients with HCV genotype 1 infection that includes protease inhibitor-based triple therapy will reduce the cumulative incidence of cirrhosis by 17.7% and mortality by 9.7% overall. The smallest reduction is predicted for Italy (incidence reduced by 10.1% and mortality by 5.4%) and the highest is for France (reductions of 34.3% and 20.7%, respectively). Although HCV infection is treated with the same therapies in different countries, the effects of the therapies on morbidity and mortality vary significantly. In addition to common guidelines that are based on virologic response-guided therapy, there is a need for public health policies based on population-guided therapy.

Impact of delayed diagnosis time in estimating progression rates to hepatitis C virus-related cirrhosis and death

Delay of the diagnosis of hepatitis C virus (HCV), and its treatment to avert cirrhosis, is often present sincethe early stage of HCV progression is latent. Current methods to determine the incubation time to HCV-related cirrhosis and the duration time from cirrhosis to subsequent events (e.g. complications or death) used to be based on the time of liver biopsy diagnosis and ignore this delay which led to an interval censoring for the first event time and a double censoring for the subsequent event time. To investigate the impact of this delay in estimating HCV progression rates and relevant estimating bias, we present a correlated two-stage progression model for delayed diagnosis time and fit the developed model to the previously studied hepatitis C cohort data from Edinburgh. Our analysis shows that taking the delayed diagnosis into account gives a mildly different estimate of progression rate to cirrhosis and significantly lower estimated progression rate to HCV-related death in comparison with conventional modelling. We also find that when the delay increases, the bias in estimating progression increases significantly.

Neutralizing Antibodies to Hepatitis C Virus in Perinatally Infected Children Followed Up Prospectively

Little is known about the presence and role of neutralizing antibodies (NtAbs) in perinatal hepatitis C virus (HCV) infection. Using HCV pseudoparticles, NtAbs were studied longitudinally in 12 HCV-infected children with or without evidence of acute hepatitis during the first year of life. Broadly reactive NtAbs of maternal origin did not prevent vertical HCV transmission or progression to chronicity. NtAbs against homologous genotype or subtype appeared during the chronic phase and were more abundant and sustained in children with acute hepatitis. Cross-reactive NtAbs were present in both groups of children, but their appearance did not correlate with better control of viremia or HCV clearance.