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Methods: We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed)., Results: We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35 ± 4 ms), transverse relaxation time (T2, 2.5 ± 0.8 ms; T2* 3.0 ± 0.7 ms), and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow., Conclusion: For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms., Key Points: • DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis. • Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance. • The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms.

Virus infections cause diseases of different severity ranged from mild infection e.g. common cold into life threatening diseases e.g. Human Immunodeficiency virus (HIV), Hepatitis B. Virus infections represent 44% of newly emerging infections. Although there are many efficient antiviral agents, they still have drawbacks due to accumulation at off target organs and developing of virus resistance due to virus mutation. Therefore, developing a delivery system that can selectively target drug into affected organs and avoid off target accumulation would be a highly advantageous strategy to improve antiviral therapy. Nanoparticles (NP) can be effectively targeted to the liver, and therefore it could be used for improving therapy of hepatic virus infections including hepatitis B virus and hepatitis C virus (HCV). Many studies were performed to encapsulate antiviral agents into nano-delivery system to improve their pharmacokinetics parameters to have a better therapeutic efficacy with lower side effects. However, the effect of virus infection on the uptake of NP has not yet been studied in detail. The latter is a crucial area as modulation of endocytic uptake of nanoparticles could impact on reduce potential therapeutic usefulness of antiviral agents loaded into nano-delivery system. In this study, a fluorescently-labelled polymeric nanoparticle was prepared and used to track NP uptake into Huh7.5, human hepatoma cells transfected with replicating HCV genomes, compared with non-transfected cells as a model representing hepatocyte uptake. Confocal microscopy and flow cytometry of virus transfected Huh7.5 cells unexpectedly demonstrated two-fold increase in uptake of NP compared to non-transfected cells. Therefore, virus transfection enhanced NP uptake into Huh7.5 cells and NP could be considered as a promising delivery system for targeted treatment of hepatitis viruses., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: This study assesses whether pegylated interferon and ribavirin is cost-effective compared with no antiviral treatment provided in routine clinical practice, for different patient subgroups., Methods: The cost-effectiveness analysis (CEA) uses a Markov decision model to estimate the lifetime cost per quality-adjusted life-year (QALY) of antiviral treatment compared with no treatment. The model is populated with data on sustained virological responses, costs, and transition probabilities all taken from a large representative sample of UK cases and centers (Trent HCV database)., Results: The CEA found that pegylated interferon and ribavirin was cost-effective for most patient subgroups. The CEA found that for patients with genotype non-1, the intervention led to cost reductions and gains of at least 0.5 QALYs. For genotype 1 cases with mild or moderate disease, and younger cirrhotic patients (aged 40 or less), costs per QALY remained below 20,000 pound sterling ($40,000 or 29,000 euro). For genotype 1 cases with cirrhosis aged 50, the mean cost per QALY rose to over 60,000 pound sterling ($120,000 or 87,000 euro)., Conclusions: The study concludes that, based on cost and effectiveness data collected from routine clinical practice, treatment with pegylated interferon and ribavirin is generally cost-effective. The study shows that there are variations according to patient subgroup and for older (aged 50 or over) genotype 1 patients with cirrhosis, antiviral treatment appears less cost-effective.

Background: Injecting drug use is the main risk factor for hepatitis C virus (HCV) infection. Secondary-care-based strategies for the management of HCV do not effectively target this vulnerable population., Aims: To evaluate the feasibility, safety and efficacy of a primary-care-based model for the delivery of HCV services including anti-viral therapy to injecting drug users., Methods: A partnership between a clinical nurse specialist employed by, and working under the supervision of, a secondary-care-based hepatitis service and drug workers and general practitioners. Three hundred and fifty-three clients attending opiate substitution clinics in primary care were evaluated. Outcomes were: number of new diagnoses of HCV infection, number of clients assessed as suitable for anti-viral treatment, and number of patients treated., Results: 174 HCV antibody positive clients were identified. Of these, 124 were chronically infected with HCV of whom only six had been previously identified. Of 118 new chronically-infected individuals, 86 entered the care pathway, 43 were assessed as suitable for anti-viral treatment and 30 have so far been treated. Outcomes of anti-viral treatment are comparable with those obtained in secondary care settings., Conclusion: A primary-care-based model offers a new paradigm for the treatment of HCV in injecting drug users., (© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd.)

Evidence for efficacy of established treatment guidelines for chronic hepatitis C virus (HCV) disease is based on multinational randomized controlled trials (RCTs). Strategies for managing HCV, however, require an assessment of the effectiveness of intervention in routine clinical practice. We report the outcomes of combination therapy in a large cohort of HCV-infected individuals in the UK. A total of 347 (113 genotype 1, 234 genotype non-1) patients were treated with pegylated interferon and ribavirin according to current guidelines. Forty-two (37.2%) of those with genotype 1 infection and 164 (70.1%) with genotype non-1 infection achieved sustained viral response (SVR). Thirty-nine (11%) patients withdrew from treatment. In addition to viral genotype, factors predictive of a response to therapy were age at start of treatment and disease stage on pretreatment liver biopsy. Multivariate regression analysis demonstrated that the effects of age [odds ratio 0.5; 95% confidence interval (0.31-0.82) per 10-year increment (P = 0.006)] were confined to genotype 1 disease. In order to further inform the management of the individual patient, a multivariate logistic model was used to predict the probability of SVR for subgroups defined by disease stage, genotype and age at commencement of therapy. This model revealed striking differences in predicted response rates between subgroups and provided a strong rationale for early treatment, particularly for those with genotype 1 disease. Our study demonstrates that results comparable with those of RCTs can be achieved in clinical practice, and suggests that prediction of response rates based on probability modelling will provide a valuable adjunct to individual patient management.

Introduction and Aims: Direct acting antiviral (DAA) treatment can reduce hepatitis C virus (HCV) infection incidence and mortality, although large scale uptake of these treatments is necessary to achieve those reductions. Targeting people who inject drugs (PWID) will be crucial to achieve the necessary reductions. Previously, treatment uptake has been very low (1-2%) among PWID, but these new DAAs have been subsidised in Australia since March 2016. This study describes treatment uptake among a sample of PWID in Australia and examines sociodemographic and drug use variables associated with treatment uptake., Design and Methods: An Australian national cross-sectional sample (n = 817) of regular PWID drawn from a convenience sentinel sample aged ≥18 years. Information on demographics, drug use, HCV antibody testing, RNA testing, recent DAA treatment initiation and DAA prescriber settings was collected via an interviewer-administered survey., Results: There were 291 HCV RNA positive participants, of who one-third reported initiating DAA treatment since the introduction of subsidised DAA medications. Current opioid substitution treatment was significantly associated with increased treatment uptake (adjusted odds ratio 2.20, 95% confidence interval 1.31, 3.68) while those with unstable housing were less likely to initiate treatment (adjusted odds ratio 0.42, 95% confidence interval 0.22, 0.82)., Discussion and Conclusions: This study found that DAA treatment uptake has increased among current PWID, a priority population for treatment. Efforts to maintain this uptake through linking current PWID with treatment providers through harm reduction services such as opioid substitution therapy, needle and syringe programs, and outreach services are required to meet incidence and mortality reduction targets., (© 2018 Australasian Professional Society on Alcohol and other Drugs.)

Background and aims: The INTRO‐HCV randomized controlled trial conducted in Norway over 2017–2019 found that integrated treatment, compared with standard‐of‐care hospital treatment, for hepatitis C virus (HCV) with direct‐acting antivirals (DAAs) improved treatment outcomes among people who inject drugs (PWID). We evaluated cost‐effectiveness of the INTRO‐HCV intervention. Design: A Markov health state transition model of HCV disease progression and treatment with cost‐effectiveness analysis from the health‐provider perspective. Primary cost, utility, and health outcome data were derived from the trial. Costs and health benefits (quality‐adjusted life‐years, QALYs) were tracked over 50 years. Probabilistic and univariate sensitivity analyses investigated DAA price reductions and variations in HCV treatment and disease care cost assumptions, using costs from different countries (Norway, United Kingdom, United States, France, Australia). Setting and participants: PWID attending community‐based drug treatment centers for people with opioid dependence in Norway. Measurements Incremental cost‐effectiveness ratio (ICER) in terms of cost per QALY gained, compared against a conventional (€70 000/QALY) willingness‐to‐pay threshold for Norway and lower (€20 000/QALY) threshold common among high‐income countries. Findings Integrated treatment resulted in an ICER of €13 300/QALY gained, with 99% and 71% probability of being cost‐effective against conventional and lower willingness‐to‐pay thresholds, respectively. A 30% lower DAA price reduced the ICER to €6 900/QALY gained, with 91% probability of being cost‐effective at the lower willingness‐to‐pay threshold. A 60% and 90% lower DAA price had 36% and >99% probability of being cost‐saving, respectively. Sensitivity analyses suggest integrated treatment was cost‐effective at the lower willingness‐to‐pay threshold (>60% probability) across different assumptions on HCV treatment and disease care costs with 30% DAA price reduction, and became cost‐saving with 60%–90% price reductions. Conclusions: Integrated hepatitis C virus treatment for people who inject drugs in community settings is likely cost‐effective compared with standard‐of‐care referral pathways in Norway and may be cost‐saving in settings with particular characteristics. [ABSTRACT FROM AUTHOR]

Background: Host factors of influenza virus replication are often found in key topological positions within protein-protein interaction networks. This work explores how protein states can be manipulated through controllability analysis: the determination of the minimum manipulation needed to drive the cell system to any desired state. Here, we complete a two-part controllability analysis of two protein networks: a host network representing the healthy cell state and an influenza A virus-host network representing the infected cell state. In this context, controllability analyses aim to identify key regulating host factors of the infected cell's progression. This knowledge can be utilized in further biological analysis to understand disease dynamics and isolate proteins for study as drug target candidates. Results: Both topological and controllability analyses provide evidence of wide-reaching network effects stemming from the addition of viral-host protein interactions. Virus interacting and driver host proteins are significant both topologically and in controllability, therefore playing important roles in cell behavior during infection. Functional analysis finds overlap of results with previous siRNA studies of host factors involved in influenza replication, NF-kB pathway and infection relevance, and roles as interferon regulating genes. 24 proteins are identified as holding regulatory roles specific to the infected cell by measures of topology, controllability, and functional role. These proteins are recommended for further study as potential antiviral drug targets. Conclusions: Seasonal outbreaks of influenza A virus are a major cause of illness and death around the world each year with a constant threat of pandemic infection. This research aims to increase the efficiency of antiviral drug target discovery using existing protein-protein interaction data and network analysis methods. These results are beneficial to future studies of influenza virus, both experimental and computational, and provide evidence that the combination of topology and controllability analyses may be valuable for future efforts in drug target discovery. [ABSTRACT FROM AUTHOR]

Summary: Little is known about engagement and retention in care of people diagnosed with chronic hepatitis C (HCV) in England. Establishing a cascade of care informs targeted interventions for improving case finding, referral, treatment uptake and retention in care. Using data from the sentinel surveillance of blood‐borne virus (SSBBV) testing between 2005 and 2014, we investigate the continuum of care of those tested for HCV in England. Persons ≥1 year old with an anti‐HCV test and subsequent RNA tests between 2005 and 2014 reported to SSBBV were collated. We describe the cascade of care, as the patient pathway from a diagnostic test, referral into care, treatment and patient outcomes. Between 2005 and 2014, 2 390 507 samples were tested for anti‐HCV, corresponding to 1 766 515 persons. A total of 53 038 persons (35 190 men and 17 165 women) with anti‐HCV positive were newly reported to SSBBV. An RNA test was conducted on 77.0% persons who were anti‐HCV positive, 72.3% of whom were viraemic (RNA positive) during this time period, 21.4% had evidence of treatment and 3130 49.5% had evidence of a sustained virological response (SVR). In multivariable models, confirmation of viraemia by RNA test varied by age and region/test setting; evidence of treatment varied by age, year of test and region/test setting; and SVR varied by age, year of test and region/setting of test. In conclusion, our findings provide HCV cascade of care estimates prior to the introduction of direct acting antivirals. These findings provide important baseline cascade estimates to benchmark progress towards elimination of HCV as a major public health threat. [ABSTRACT FROM AUTHOR]

Background: Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany. Material and Methods: We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness. Results: Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses. Conclusions: Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C treatment uptake in Australia is low. To increase access to hepatitis C virus treatment for people who inject drugs, we developed a community-based, nurse-led service that linked a viral hepatitis service in a tertiary hospital to primary care clinics, and resulted in hepatitis C treatment provision in the community. Methods: A retrospective cohort study of patients referred to the community hepatitis service was undertaken to determine the cascade of care. Logistic regression analyses were used to identify predictors of hepatitis C treatment uptake. Results: Four hundred and sixty-two patients were referred to the community hepatitis service; 344 attended. Among the 279 attendees with confirmed chronic hepatitis C, 257 (99%) reported ever injecting drugs, and 124 (48%) injected in the last month. Of 201 (72%) patients who had their fibrosis staged, 63 (31%) had F3-F4 fibrosis. Fifty-five patients commenced hepatitis C treatment; 26 (47%) were current injectors and 25 (45%) had F3-F4 fibrosis. Nineteen of the 27 (70%) genotype 1 patients and 14 of the 26 (54%) genotype 3 patients eligible for assessment achieved a sustained virologic response. Advanced fibrosis was a significant predictor of treatment uptake in adjusted analysis (AOR 2.56, CI 1.30–5.00, p = 0.006). Conclusions: Our community hepatitis service produced relatively high rates of fibrosis assessment, hepatitis C treatment uptake and cure, among people who inject drugs. These findings highlight the potential benefits of providing community-based hepatitis C care to people who inject drugs in Australia–benefits that should be realised as direct-acting antiviral agents become available. [ABSTRACT FROM AUTHOR]

In clinical trials, sofosbuvir showed high antiviral activity in patients infected with hepatitis C virus (HCV) across all genotypes. We aimed to determine the cost-effectiveness of sofosbuvir-based treatment compared to current standard treatment in mono-infected patients with chronic hepatitis C (CHC) genotypes 1–4 in Switzerland. Cost-effectiveness was modelled from the perspective of the Swiss health care system using a lifetime Markov model. Incremental cost-effectiveness ratios (ICERs) used an endpoint of cost per quality-adjusted life year (QALY) gained. Treatment characteristics, quality of life, and transition probabilities were obtained from published literature. Country-specific model inputs such as patient characteristics, mortality and costs were obtained from Swiss sources. We performed extensive sensitivity analyses. Costs and effects were discounted at 3% (range: 0–5%) per year. Sofosbuvir-containing treatment in mixed cohorts of cirrhotic and non-cirrhotic patients with CHC genotypes 1–4 showed ICERs between CHF 10,337 and CHF 91,570 per QALY gained. In subgroup analyses, sofosbuvir dominated telaprevir- and boceprevir-containing treatment in treatment-naïve genotype 1 cirrhotic patients. ICERs of sofosbuvir were above CHF 100,000 per QALY in treatment-naïve, interferon eligible, non-cirrhotic patients infected with genotypes 2 or 3. In deterministic and probabilistic sensitivity analyses, results were generally robust. From a Swiss health care system perspective, treatment of mixed cohorts of cirrhotic and non-cirrhotic patients with CHC genotypes 1–4 with sofosbuvir-containing treatment versus standard treatment would be cost-effective if a threshold of CHF 100,000 per QALY was assumed. [ABSTRACT FROM AUTHOR]

Hepatitis C virus ( HCV) antiviral treatment for people who inject drugs ( PWID) could prevent onwards transmission and reduce chronic prevalence. We assessed current PWID treatment rates in seven UK settings and projected the potential impact of current and scaled-up treatment on HCV chronic prevalence. Data on number of PWID treated and sustained viral response rates ( SVR) were collected from seven UK settings: Bristol (37-48% HCV chronic prevalence among PWID), East London (37-48%), Manchester (48-56%), Nottingham (37-44%), Plymouth (30-37%), Dundee (20-27%) and North Wales (27-33%). A model of HCV transmission among PWID projected the 10-year impact of (i) current treatment rates and SVR (ii) scale-up with interferon-free direct acting antivirals ( IFN-free DAAs) with 90% SVR. Treatment rates varied from <5 to over 25 per 1000 PWID. Pooled intention-to-treat SVR for PWID were 45% genotypes 1/4 [95% CI 33-57%] and 61% genotypes 2/3 [95% CI 47-76%]. Projections of chronic HCV prevalence among PWID after 10 years of current levels of treatment overlapped substantially with current HCV prevalence estimates. Scaling-up treatment to 26/1000 PWID annually (achieved already in two sites) with IFN-free DAAs could achieve an observable absolute reduction in HCV chronic prevalence of at least 15% among PWID in all sites and greater than a halving in chronic HCV in Plymouth, Dundee and North Wales within a decade. Current treatment rates among PWID are unlikely to achieve observable reductions in HCV chronic prevalence over the next 10 years. Achievable scale-up, however, could lead to substantial reductions in HCV chronic prevalence. [ABSTRACT FROM AUTHOR]

Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response. Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients. [ABSTRACT FROM AUTHOR]

Based on meta-analysis, the higher the proportion of addiction-treated patients, the higher the treatment completion rate. The rate of sustained virologic response rate in drug users is very similar to that in the general population.Background. Hepatitis C virus (HCV)–infected drug users (DUs) have largely been excluded from HCV care. We conducted a systematic review and meta-analysis of the literature on treatment completion and sustained virologic response (SVR) rates in DUs. We assessed the effects of different treatment approaches and services to promote HCV care among DUs as well as demographic and viral characteristics.Methods. Studies of at least 10 DUs treated with pegylated interferon/ribavirin that reported SVR were analyzed. Heterogeneity was assessed (Cochran test) and investigated (meta-regression), and pooled rates were estimated (random effects).Results. Thirty-six studies comprising 2866 patients were retrieved. The treatment completion rate among DUs was 83.4% (95% confidence interval [CI], 77.1%–88.9%). Among studies that included addiction-treated and untreated patients during HCV therapy, the higher the proportion of addiction-treated patients, the higher the HCV treatment completion rate (P < .0001). After adjusting for human immunodeficiency virus (HIV)/HCV coinfection, sex, and treatment of addiction, support services during antiviral therapy increased treatment completion (P < .0001). The pooled SVR rate was 55.5% (95% CI, 50.6%–60.3%). Genotype 1/4 (P = .0012) and the proportion of HIV-coinfected DUs (P = .0173) influenced the SVR rate. After adjusting for HCV genotype 1/4 and HIV/HCV coinfection, the SVR rate was positively correlated with involvement of a multidisciplinary team (P < .0001).Conclusions. Treatment of addiction during HCV therapy results in higher treatment completion. Our pooled SVR rate is similar to that obtained in registration trials in the general population. Treatment of addiction during HCV therapy will likely be important for HCV-infected DUs undergoing treatment with more complex regimens including direct-acting antivirals. [ABSTRACT FROM PUBLISHER]

With the arrival of simple, efficient and safe interferon-free treatment regimens, hepatitis C virus ( HCV) therapy will have the potential to be successfully used for the majority of infected patients and prevent the associated morbidity and mortality. With the current treatment uptake rates, only a very small proportion of HCV-infected patients are reached. Paradoxically, treatment rates are lowest in the most affected at-risk group - people who inject drugs ( PWID) - which is the major driving force behind the spread of HCV infection. To conquer the increasing problem of HCV-related liver disease, many existing but modifiable obstacles, which prevent detection, assessment and treatment uptake, have to be overcome in this population. This review article summarizes the existing literature on the most relevant barriers preventing HCV care and describes measures to overcome these obstacles. [ABSTRACT FROM AUTHOR]

HIV/HCV coinfected individuals under highly active antiretroviral therapy (HAART) represent an interesting model for the investigation of the role played by the immune system in driving the evolution of the HCV quasispecies. We prospectively studied the intra-host evolution of the HCV heterogeneity in 8 coinfected subjects, selected from a cohort of 32 patients initiating HAART: 5 immunological responders (group A) and 3 immunological non-responders (group B), and in two HCV singly infected controls not assuming drugs (group C). For all these subjects at least two serial samples obtained at the first observation (before HAART) and more than 1 year later, underwent clonal sequence analysis of partial E1/E2 sequences, encompassing the whole HVR1. Evolutionary rates, dated phylogenies and population dynamics were co-estimated by using a Bayesian Markov Chain Monte Carlo approach, and site specific selection pressures were estimated by maximum likelihood-based methods. The intra-host evolutionary rates of HCV quasispecies was 10 times higher in subjects treated with HAART than in controls without immunodeficiency (1.9 and 2.3x10-3 sub/site/month in group A and B and 0.29x10-3 sub/site/month in group C individuals). The within-host Bayesian Skyline plot analysis showed an exponential growth of the quasispecies populations in immunological responders, coinciding with a peak in CD4 cell counts. On the contrary, quasispecies population remained constant in group B and in group C controls. A significant positive selection pressure was detected in a half of the patients under HAART and in none of the group C controls. Several sites under significant positive selection were described, mainly included in the HVR1. Our data indicate that different forces, in addition to the selection pressure, drive an exceptionally fast evolution of HCV during HAART immune restoration. We hypothesize that an important role is played by the enlargement of the viral replicative space. [ABSTRACT FROM AUTHOR]

A significant number of patients with chronic hepatitis C infection have minimal fibrosis at presentation. Although the short-term outlook for such patients is good, there are limited data available on long-term progression. We assessed the risk of fibrosis progression in 282 patients with chronic hepatitis C with Ishak stage 0 or 1 fibrosis on initial liver biopsy. Progression of fibrosis stage occurred in 118 patients (42%) over a median interval of 52.5 months. Thirteen (5%) progressed to severe (Ishak stage 4 or more) fibrosis. Progression was significantly associated with both age at initial biopsy [odds ratio (OR) for progression of 1.31 per 10 year increase in age] and median alanine transaminase (ALT) levels during follow-up (OR of 1.06 per 10 IU/L increase). There was no significant association with gender, histological inflammatory grade, hepatic steatosis or body mass index. We conclude that hepatitis C with initially mild fibrosis does progress in a substantial proportion of patients and should not be viewed as a benign disease. Early antiviral therapy should be considered in older patients and those with high ALT levels. [ABSTRACT FROM AUTHOR]

Predictive factors for initiation of antiviral therapy in chronically infected hepatitis C virus (HCV) patients are not fully elucidated. The aim of this study was to determine predictive factors for initiation of treatment with standard or pegylated interferon either alone or combined with ribavirin. A Danish cohort of individuals chronically infected with HCV was used and observation time was calculated from the date of inclusion in the cohort to date of death, last clinical observation, 1 January 2007, or start of HCV antiviral treatment in treatment-naïve patients. Kaplan–Meier survival analysis was used to construct time to event curves. Cox regression was used to determine the incidence rate ratios as estimates of relative risk (RR) and 95% confidence intervals (CI). A total of 1780 patients were enrolled in the study. The cumulative chance of treatment initiation over 5 years was 33.0%. We found several strong predictors of treatment initiation: elevated alanine aminotransferase [>2 times upper limit (RR = 2.17, 95% CI 1.64–2.87), >3 times upper limit (RR = 3.64, 95% CI 2.75–4.81)], genotype 2 or 3 (RR = 1.86, 95% CI 1.49–2.31) and HIV co-infection (RR = 0.28, 95% CI 0.15–0.53). To our knowledge, this study is the first to estimate factors predicting initiation of antiviral treatment in patients with chronic HCV infection on a nationwide scale. We found that several of the factors predicting initiation of antiviral treatment correlate with factors known to predict a better response to treatment and factors known to increase the progression of liver disease. [ABSTRACT FROM AUTHOR]

We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures. [ABSTRACT FROM AUTHOR]

Monitoring of HCV-RNA in blood during antiviral therapy is performed mostly by commercially available reverse transcription polymerase chain reaction-based (RT-PCR) assays, with a lower detection limit of 30–50 IU/mL of HCV-RNA. Use of different tests in the pivotal trials of combination therapy has generated some discordance, in terms of predictive value of the early virological response (EVR). To evaluate whether the use of a more sensitive test, as a qualitative assay based on transcription mediated amplification (TMA) with a lower detection limit of 5–10 IU/mL of HCV-RNA, may obtain a better prediction of EVR and of the ultimate virological outcome, we retrospectively evaluated serial samples from 108 naïve patients with HCV genotype 1 chronic hepatitis, treated with pegylated α2b interferon plus ribavirin for 48 weeks and with a 24 weeks stopping rule. Serum samples of patients, obtained during treatment at weeks 4, 12, 24 and 48 and after treatment at week 24, were evaluated by TMA. Comparison of the RT-PCR and TMA assays for the qualitative detection of HCV-RNA showed no significant differences in performance when these tests were used at the end of the treatment period for assessing patients without an on-treatment virological response and those who eventually obtain a sustained virological response. Our results show instead that the use of TMA assay to detect HCV-RNA at 12 and 24 weeks of the combination therapy is more effective than RT-PCR in identifying patients with the highest probability of sustained HCV-RNA clearance. [ABSTRACT FROM AUTHOR]

The hepatitis C virus RNA polymerase (NS5B) is strictly required for viral replication and thus represents an attractive target for antiviral drug development. In this study, stable HeLa cell lines with an integrated NS5B gene were selected by G418 and then confirmed by genome PCR. Subsequently, transcription and expression of the integrated NS5B genes were demonstrated by RT-PCR and Western blot analysis. Further analysis demonstrated enzymatic activity of the expressed NS5B polymerase. The stable HeLa cell lines should be useful for the identification of NS5B inhibitors and for studying the mechanisms of HCV replication. [ABSTRACT FROM AUTHOR]

Analysis of the genome of human herpesvirus 8 (HHV-8) led to the discovery of several novel genes, unique among the characterized gammaherpesviruses. These include cytokines (interleukin-6 and chemokine homologues), two putative signal-transducing transmembrane proteins encoded by genes K1 and K15 at the genome termini, and an OX-2 (CD200) receptor homologue that had not previously been identified in a gammaherpesvirus. HHV-8 also specifies a diverged version of the gammaherpesvirus-conserved G protein-coupled chemokine receptor (vGCR) and a latently expressed protein unique to HHV-8 specified by open reading frame (ORF) K12. These cytokine and receptor homologues mediate signal transduction or modulate the activities of other endogenous cytokines and receptors to enhance viral productive replication, regulate latent-lytic switching, evade host attack, or mediate cell survival. The viral signalling ligands and receptors are also potential contributors to virus-associated diseases, Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, and so represent potentially important targets for therapeutic and antiviral drugs. Understanding these proteins' modes of action and functions in viral biology and disease is therefore of considerable importance, and the subject of this review. [ABSTRACT FROM AUTHOR]

Discusses the antiviral therapy for chronic viral hepatitis. Three major forms of chronic viral hepatitis; Functions of interferons; Advantages of the development of sensitive and specific assays for components of hepatitis viruses in the serum and liver.