A mathematical model by route of transmission and fibrosis progression to estimate undiagnosed individuals with HCV in different Italian regions.

BACKGROUND: Although an increase in hepatitis C virus (HCV) prevalence from Northern to Southern Italy has been reported, the burden of asymptomatic individuals in different Italian regions is currently unknown. METHODS: A probabilistic approach, including a Markov chain for liver disease progression, was applied to estimate current HCV viraemic burden. The model defined prevalence by geographic area using an estimated annual historical HCV incidence by age, treatment rate, and migration rate from the Italian National database. Viraemic infection by age group was estimated for each region by main HCV transmission routes of individuals for stage F0-F3 (i.e. patients without liver cirrhosis and thus potentially asymptomatic) and F4 (patients with liver cirrhosis, thus potentially symptomatic). RESULTS: By January 2020, it was estimated that there were 409,184 Italian individuals with HCV (prevalence of 0.68%; 95% CI: 0.54-0.82%), of which 300,171 (0.50%; 95% CI: 0.4-0.6%) were stage F0-F3. Considering all individuals with HCV in stage F0-F3, the geographical distributions (expressed as the proportion of HCV infected individuals by macroarea within the overall estimated number of F0-F3 individuals and prevalence values, expressed as the percentage of individuals with HCV versus the overall number of individuals for each macroarea) were as follows: North 42.1% (0.45%; 95% CI: 0.36-0.55%), Central 24.1% (0.61%; 95% CI: 0.48-0.74%), South 23.2% (0.50%; 95% CI: 0.4-0.61%), and the Isles 10.6% (0.49%; 95% CI: 0.39-0.59%). The population of people who inject drugs accounted for 50.4% of all individuals infected (F0-F3). Undiagnosed individuals (F0-F3) were ~ 15 years younger (⁓ 50 years) compared with patients with stage F4 (⁓ 65 years), with similar age distributions across macroareas. In contrast to what has been reported on HCV epidemiology in Italy, an increasing trend in the proportion of potentially undiagnosed individuals with HCV (absolute number within the F0-F3) from South (23.2%) to North (42.1%) emerged, independent of similar regional prevalence values. CONCLUSION: This targeted approach, which addresses the specific profile of undiagnosed individuals, is helpful in planning effective elimination strategies by region in Italy and could be a useful methodology for other countries in implementing their elimination plans.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.

BACKGROUND & AIMS: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. METHODS: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. RESULTS: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). CONCLUSIONS: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. LAY SUMMARY: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study.

BACKGROUND & AIMS: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. METHODS: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ±â€¯197.6 days. RESULTS: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. CONCLUSIONS: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors. LAY SUMMARY: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Modeling cost-effectiveness and health gains of a "universal" versus "prioritized" hepatitis C virus treatment policy in a real-life cohort.

We evaluated the cost-effectiveness of two alternative direct-acting antiviral (DAA) treatment policies in a real-life cohort of hepatitis C virus-infected patients: policy 1, "universal," treat all patients, regardless of fibrosis stage; policy 2, treat only "prioritized" patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virus-infected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policies' cost-effectiveness. The patients' age and fibrosis stage, assumed DAA treatment cost of €15,000/patient, and the Italian liver disease costs were used to evaluate quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country-specific health states costs and mean treatment cost of €30,000. For the Italian base-case analysis, the cost-effective ICER obtained using policy 1 was €8,775/QALY. ICERs remained cost-effective in 94%-97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was €19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0-F3 post-sustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost-saving for the base price (€15,000) discounts of at least 75% applied in patients with F0-F2 fibrosis. CONCLUSION: Extending hepatitis C virus treatment to patients in any fibrosis stage improves health outcomes and is cost-effective; cost-effectiveness significantly increases when lowering treatment prices in early fibrosis stages. (Hepatology 2017;66:1814-1825).

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model.

Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett's Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side-to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.

Increased incidence of liver cancer after successful DAA treatment of chronic hepatitis C: Fact or fiction?

Therapy of hepatitis C has been revolutionized by Direct Antiviral Agents. These drugs are safe and efficacious in all infected patients, including those with advanced, or decompensated cirrhosis, and are currently largely used in such cases in clinical practice worldwide. It was therefore cause of great concern the publication of two reports suggesting that treatment with DAAs could increase the risk of hepatocellular carcinoma in cirrhotic patients, particularly in those receiving antiviral therapy after having been cured for an HCC. These reports have generated a great and controversial debate and have been followed by a series of other publications not confirming such increased risk. This article summarizes published studies assessing the relation between DAA therapy and HCC in two different clinical setting: HCC recurrence in patients with an history of cured HCC and "de novo" HCC occurrence in patients without previous HCC. Rates of HCC recurrence after DAAs were extremely variable in different studies, reflecting great heterogeneity of this clinical setting. Data on "de novo" HCC incidence were more homogeneous and suggest that treatment with DAAs is not modifying the risk of developing HCC in the first 6-12 months. The possibility that treatment with DAAs may favour tumour growth and spread in individual patients with active HCC foci is suggested by some observations but remains unproven. There is clearly a need for prospective studies designed to better define these issues.

Literature review of the distribution of hepatitis C virus genotypes across Europe.

Recent advances in hepatitis C virus (HCV) therapies have transformed the treatment landscape for this disease. However, efficacy of current treatments depends on HCV genotype and individual patient characteristics. This review aimed to appraise observational studies reporting epidemiological outcomes to characterize HCV genotype distribution in Europe, in the general HCV population and various subpopulations of interest. MEDLINE and EMBASE entries published between November 2008 and November 2013 were systematically searched. Studies were grouped according to the patient populations of interest: general HCV population, HCV-HIV co-infected patients, patients with advanced fibrosis/cirrhosis, and liver transplant recipients. Thirty publications provided estimates of HCV genotype distribution in four distinct patient groups: general HCV population (n = 21), HCV-HIV co-infected patients (n = 6), liver transplant patients (n = 3), and patients with HCV-compensated cirrhosis (n = 1). Nationwide estimates of genotype distribution in the general HCV population were available for 10 countries, with genotypes 1 and 3 the most commonly reported. Romanian studies were found to have reported genotype 1 infections almost exclusively (98.0-99.8%). Considerable regional variation was reported in some countries (e.g., Italy), but not others (e.g., France). National and multi-national estimates for the HCV-HIV co-infected population suggested a different genotype distribution to that in the general HCV population. No studies reported nationwide genotype distribution in patients with advanced liver disease. Given the clinical importance of genotype in developing optimal HCV eradication strategies, further nationwide European studies are needed to fully characterize genotype distribution in both the general HCV population and in HCV subpopulations. J. Med. Virol. 88:2157-2169, 2016. © 2016 Wiley Periodicals, Inc.

Protease inhibitors-based therapy induces acquired spherocytic-like anaemia and ineffective erythropoiesis in chronic hepatitis C virus patients.

BACKGROUND & AIMS: The addition of protease inhibitors, boceprevir (BOC) or telaprevir (TRV), to peg-interferon and ribavirin (PR) increases the incidence of anaemia in patients with chronic hepatitis C virus (HCV) infection. Although genetic variants in inosine triphosphatase (ITPA) gene have been linked to the haemolytic anaemia induced by PR, the mechanism sustaining severe anaemia during triple therapy is still unknown. This study aims to elucidate the molecular mechanisms underlying anaemia in chronic HCV patients with combined therapy. METHODS: We studied 59 patients with chronic HCV genotype-1: 29 treated with TRV/PR and 30 with BOC/PR. We evaluated biochemical and haematological parameters, red cell index at baseline, 4, 12, 16 and 24 weeks of treatment; in a subgroup, we performed functional studies: osmotic fragility, red cell membrane protein separation, mass spectrometry analysis, quantification of erythroid microparticles release. IL28B and ITPA polymorphisms were also evaluated. RESULTS: We found early acute normochromic normocytic haemolytic anaemia (4-8 weeks) followed by a late macrocytic hypo-regenerative anaemia with inappropriate low reticulocyte count (12-24 weeks). Studies on red cells revealed: (i) presence of spherocytes; (ii) increased osmotic fragility; (iii) abnormalities in red cell membrane protein composition; (iv) reduced membrane-cytoskeleton stability; (v) increased release of erythroid microparticles. ITPA polymorphisms impacted only the early phase of anaemia. CONCLUSIONS: The bimodal pattern of anaemia in chronic HCV patients on triple therapy might be because of acquired spherocytic-like anaemia in the early phase, followed by hyporegenerative anaemia, most likely related to the combined effects of PR and TRV or BOC on erythropoiesis.

Adherence to WCRF/AICR lifestyle recommendations for cancer prevention and the risk of Barrett's esophagus onset and evolution to esophageal adenocarcinoma: results from a pilot study in a high-risk population.

PURPOSE: While adherence to the World Cancer Research Fund (WCRF) guidelines on lifestyle and cancer was recently proven to be associated with an increased risk of esophageal cancer, no investigation has yet been carried out on its role on Barrett's esophagus (BE) development and its progression to esophageal adenocarcinoma (EAC). The primary aim of this study was to evaluate the role of adherence to WCRF lifestyle recommendations in BE onset and progression. The secondary aim was to investigate the association between disease progression and specific aspects of diet and lifestyle. METHODS: Established risk factors for BE and EAC development and adherence to WCRF guidelines were assessed in 107 consecutive patients undergoing an upper gastrointestinal endoscopy for symptoms suggesting gastroesophageal reflux (GERD) and a suspected diagnosis of BE/dysplasia on BE. Patients were divided according to histology: those with GERD without metaplasia, with non-dysplastic BE, with low-grade dysplasia, with high-grade dysplasia or with early EAC. The four groups were expressed as an ordered categorical variable of disease progression. An ordered logit model was estimated to identify the independent predictors of disease progression. RESULTS: Adherence to WCRF guidelines was identified as independent protective factor (OR 0.51, 95 % CI 0.37-0.67) of disease progression. Disease progression was associated with reduced adherence to guidelines on physical activity (from 48.2 to 5.3 %, p = 0.001), sedentary habits (from 33.3 to 0 %, p = 0.03), fruit consumption (from 37.0 to 5.6 %, p = 0.02) and processed meat consumption (from 51.9 to 10.5 %, p = 0.002). CONCLUSION: Adherence to WCRF guidelines has a protective factor in BE onset and its evolution to EAC.

Cost-effectiveness of boceprevir or telaprevir for previously treated patients with genotype 1 chronic hepatitis C.

BACKGROUND & AIMS: Randomised controlled trials (RCTs) show that triple therapy (TT) with peginterferon alfa, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon-ribavirin dual therapy (DT) in the treatment of genotype 1 (G1) chronic hepatitis C (CHC) patients with previous relapse (RR), partial response (PAR), and null-response (NR). We assess the cost-effectiveness of TT compared to no therapy in the treatment of patients previously treated with G1 CHC. METHODS: The available published literature provided the data source. The target population was made up of previously treated Caucasian patients with G1 CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euro at 2012 value), life years gained (LYG), quality adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER).The robustness of the results was evaluated by one-way deterministic and multivariable probabilistic sensitivity analyses. RESULTS: In RR patients, ICER per LYG compared to no therapy was €9555 for BOC-LEAD-IN-RR and €7910 for TVR-LEAD-IN-RR, being BOC dominated by TVR. In PAR patients, ICER for LYG was €11,947 for BOC-LEAD-IN-PAR and €14,931 for TVR-PAR, being TVR cost-effective compared to BOC (ICER for QALY €22,258). In NR patients, ICER for LYG was €26,499 for TVR-LEAD-IN-NR. The models were sensitive to likelihood of sustained virological response and to BOC/TVR prices. CONCLUSIONS: 1st generation HCV PI is highly cost-effective compared to no therapy in RR and PAR G1 CHC patients. TVR dominated BOC in RR, and was cost-effective compared to BOC in PAR patients. In NR patients an assessment of the response after a lead-in period should be performed to improve safety and cost-effectiveness.

Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: a vicious circle of clinical significance?

UNLABELLED: Insulin resistance (IR) is common in chronic hepatitis C (CHC) and associates with reduced virological response to pegylated-interferon (PEG-IFN)/ribavirin therapy, but the underlying mechanisms are still unclear. We have previously shown that, in CHC patients, insulin plasma levels are inversely related to antiviral effect induced by PEG-IFN. Therefore, we investigated the in vitro effect of insulin on interferon alpha (IFN-α) intracellular signaling as well as that of IFN-α on insulin signaling. HepG2 cells, preincubated with or without insulin, were stimulated with IFN-α2b and messenger RNA (mRNA) and protein expression of IFN-stimulated genes (ISGs) were measured at different timepoints. The role of intracellular suppressors of cytokine signaling 3 (SOCS3) was evaluated with the small interfering RNA (siRNA) strategy. To assess the effect of IFN-α on insulin signaling, HepG2 were preincubated with or without IFN before addition of insulin and cells were then analyzed for IRS-1 and for Akt/PKB Ser473 phosphorylation. Insulin (100 and 1000 nM) significantly reduced in a dose-dependent fashion IFN-induced gene expression of PKR (P=0.017 and P=0.0017, respectively), MxA (P=0.0103 and P=0.00186), and 2'-5' oligoadenylatesynthetase 1 (OAS-1) (P=0.002 and P=0.006). Insulin also reduced IFN-α-induced PKR protein expression. Although insulin was confirmed to increase SOCS3 expression, siRNA SOCS3 did not restore ISG expression after insulin treatment. IFN-α was found to reduce, in a dose-dependent fashion, IRS-1 gene expression as well as Akt/PKB Ser473 phosphorylation induced by insulin. CONCLUSION: These results provide evidence of reciprocal interference between insulin and IFN-α signaling in liver cells. These findings may contribute to understand the role of insulin in CHC: IR might be favored by endogenous cytokines including IFN-α, and the resulting hyperinsulinemia then reduces the antiviral response to exogenous IFN in a vicious circle of clinical significance.

Impact of a sustained virological response on the long-term outcome of hepatitis C.

A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA 24 weeks after withdrawal from therapy (SVR-24w), is the primary endpoint of antiviral therapy in chronic hepatitis C. There is solid evidence that patients who reach this target will remain virus free during long-term follow-up, with a risk of late HCV recurrence of <2% in published series using the most stringent criteria for assessing the virological response during and after antiviral therapy. Long-term observational studies indicate that SVR-24w has a profound impact on the natural course of chronic hepatitis C in relation to biochemical and histological remission of liver disease and improvement in quality of life. The effects of successful antiviral therapy on clinical endpoints such as the development of end-stage liver disease, its severe complications and liver-related mortality have been more difficult to ascertain because of the heterogeneity of the initial staging and rate of progression of chronic hepatitis C. However, most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival, at least in successfully treated patients who have already progressed to significant liver fibrosis or early cirrhosis. Outcome modelling suggests that these effects might also include HCV patients treated with milder forms of liver damage.

Applying a system approach to forecast the total hepatitis C virus-infected population size: model validation using US data.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with chronic progressive liver disease. Its global epidemiology is still not well ascertained and its impact will be confronted with a higher burden in the next decade. AIM: The goal of this study was to develop a tool that can be used to predict the future prevalence of the disease in different countries and, more importantly, to understand the cause and effect relationship between the key assumptions and future trends. METHODS: A system approach was used to build a simulation model where each population was modeled with the appropriate inflows and outflows. Sensitivity analysis was used to identify the key drivers of future prevalence. RESULTS: The total HCV-infected population in the US was estimated to decline 24% from 3.15 million in 2005 to 2.47 million in 2021, while disease burden will increase as the remaining infected population ages. During the same period, the mortality rate was forecasted to increase from 2.1 to 3.1%. The diagnosed population was 50% of the total infections, while less than 2% of the total infections were treated. CONCLUSION: We have created a framework to evaluate the HCV-infected populations in countries around the world. This model may help assess the impact of policies to meet the challenges predicted by the evolution of HCV infection and disease. This prediction tool may help to target new public health strategies.

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel.

BACKGROUND AND AIM: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel. METHODOLOGY: Data references were identified through indexed journals and non-indexed sources. In this work, 13,000 articles were reviewed and 860 were selected based on their relevance. RESULTS: Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (≤ 0.5%) estimates were from northern European countries and the highest (≥ 3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel. CONCLUSION: Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region.

Estimated prevalence of undiagnosed HCV infected individuals in Italy: A mathematical model by route of transmission and fibrosis progression.

BACKGROUND: The universal treatment of diagnosed patients with chronic HCV infection has been widely conducted in Italy since 2017. However, the pool of individuals diagnosed but yet to be treated in Italy has been estimated to end around 2025, leaving a significant proportion of infected individuals undiagnosed/without care. Estimates of this population are currently unknown. METHODS: A probabilistic modelling approach was applied to estimate annual historical HCV incident cases by their age-group (0-100 years) distribution from available literature and Italian National database (1952 to October 2019). Viraemic infection rates were modelled on the main infection routes in Italy: people who inject drugs (PWID), tattoos, sexual transmission, glass syringe use, blood transfusion and vertical transmission. Annual liver fibrosis stage transition probabilities were modelled using a Markov model. The number of HCV viraemic asymptomatic (fibrosis stage F0-F3:potentially undiagnosed/unlinked to care) and symptomatic (fibrosis stage F4: potentially linked to care) individuals was estimated. RESULTS: By October 2019, total viraemic HCV individuals in Italy (excluding treated patients since 1992) were estimated to be 410,775 (0.68 % of current population of Italy; 95 % CI: 0.64-0.71%, based on the current Italian population), of which 281,809 (0.47 %; 95 % CI:0.35-0.60%) were fibrosis stage F0-F3. Among different high risk groups in stage F0-F3, the following distribution was estimated: PWID; 52.0 % (95 % CI:37.9-66.6 %), tattoo; 28.8 % (95 % CI:23-32.3 %), sexual transmission; 12.0 % (95 % CI:9.6-13.7 %), glass syringe and transfusion; 6.4 % (95 % CI:2.4-17.8 %), and vertical transmission; 0.7 % (95 % CI:0.4-1.2 %). CONCLUSION: Under the assumption that most untreated HCV-infected individuals with stage F0-F3 are undiagnosed, more than 280,000 individuals are undiagnosed and/or unlinked to care in Italy. Marked heterogeneity across the major routes of HCV transmission was estimated. This modelling approach may be a useful tool to characterise the HCV epidemic profile also in other countries, based on country specific epidemiology and HCV main transmission routes.

Effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients: Results of the Italian cohort of a post-marketing observational study.

BACKGROUND AND AIMS: The MARS post-marketing, observational study evaluates glecaprevir/pibrentasvir in a large population of Italian patients who are infected with HCV. PATIENTS AND METHODS: Achievement of SVR12 was the primary endpoint in the overall population and by subpopulations of interest (treatment-naïve and treatment-experienced patients, subjects infected with different HCV genotype/sub-genotype, cirrhotic and non-cirrhotic patients, patients with different severity of fibrosis, patients with an APRI score ≥1, subjects with comorbidities, HIV-coinfected patients, elderly patients and people who use drugs). Safety and quality of life (assessed by SF-36 and Work Productivity and Activity Impairment) were also evaluated. RESULTS: The SVR12 rate was 99.4% (319/321; 95% CI: 97.8-99.8%) in the core population with sufficient follow-up (n = 321), 99.7% (289/290) in 8-week treated patients, and high (>96%) across subgroups. Only three patients (0.9%) had treatment-related adverse events that led to treatment discontinuation. In total, 30.1% of patients showed an improvement of ≥2.5 points in the Physical Component Summary of the SF-36 from baseline to the end of treatment, and this figure raised to 37.5% with the achievement of SVR12. Corresponding values for MCS were 42.2% and 42.8%, respectively. CONCLUSION: Glecaprevir/pibrentasvir is safe and effective across subpopulations who are underserved in clinical trials.

Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C.

BACKGROUND & AIMS: Non-invasive assessment of liver fibrosis is a challenging area. Several methods have been proposed in patients with chronic hepatitis C (CHC) but their performance may be improved when they are combined as suggested by recently proposed algorithms using either transient elastography (TE) and Fibrotest (FT) (Castera) or AST-to-Platelet Ratio Index (APRI) and FT (SAFE biopsy). The aim of this prospective study was to compare the performance of these two algorithms for diagnosing significant fibrosis and cirrhosis in 302 CHC patients. METHODS: All patients underwent TE, FT and APRI the same day as liver biopsy, taken as reference standard. RESULTS: Significant fibrosis (Metavir F>or=2) was present in 76% of patients and cirrhosis (F4) in 25%. TE failure was observed in eight cases (2.6%). For significant fibrosis, Castera algorithm saved 23% more liver biopsies (71.9% vs. 48.3%, respectively; p<0.0001) than SAFE biopsy but its accuracy was significantly lower (87.7% vs. 97.0%, respectively; p<0.0001). Regarding cirrhosis, accuracy of Castera algorithm was significantly higher than that of SAFE biopsy (95.7% vs. 88.7%, respectively; p<0.0001). The number of saved liver biopsies did not differ between the two algorithms (78.8% vs. 74.8%; p=NS). CONCLUSIONS: Both algorithms are effective for non-invasive staging of liver fibrosis in chronic hepatitis C. Although the number of liver biopsies avoided does not differ between algorithms for diagnosing cirrhosis, it is significantly higher with Castera algorithm than SAFE biopsy for significant fibrosis.

Prediction of oesophageal varices in hepatic cirrhosis by simple serum non-invasive markers: Results of a multicenter, large-scale study.

BACKGROUND & AIMS: Preliminary data suggest that non-invasive methods could be useful to assess presence of oesophageal varices (OV) in cirrhotic patients. We aimed to further investigate simple serum non-invasive markers for diagnosing and grading OV. METHODS: A retrospective set of 510 cirrhotics and a prospective set of 110 cirrhotics were enrolled consecutively in five centers. Platelets, AST-to-ALT ratio, AST-to-platelet-ratio index, Forns' index, Lok index, Fib-4, and Fibroindex were measured within 2 months from upper endoscopy, taken as a gold standard. Performance was expressed as sensitivity, specificity, positive, and negative predictive values (PPV, NPV), accuracy, and area under the curve (AUC). RESULTS: A combination of Lok index (cutoff=1.5) and Forns' index (cutoff=8.8) had 0.80 AUC (0.76-0.84, 95% CI), and high NPV (>90%) to exclude clinically relevant OV, defined as large OV or small OV with red signs or in Child-Pugh C cirrhosis. By applying this combination, upper endoscopy would have been avoided in 1/3 of our cirrhotics. Large OV could be excluded with 96% NPV by Lok index (cutoff=1.5). A combination of Lok index (cutoff=0.9) and Forns' index (cutoff=8.5) predicted presence of any grade OV with good performance: 0.82 AUC (0.76-0.88, 95% CI), 88% PPV. CONCLUSIONS: Serum non-invasive markers may be useful as a first line tool to identify cirrhotic patients in which the risk of clinically relevant OV is trivial, and to reduce the number of upper endoscopies. However, we are still far from the possibility of replacing upper endoscopy by simple serum non-invasive markers in the vast majority of patients.

A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C.

UNLABELLED: Fibrosis progression is the main determinant of liver disease outcome in chronic hepatitis C, being influenced by environmental and host factors. Recently, a cirrhosis risk score (CRS) based on seven single-nucleotide polymorphisms was proposed as genetic predictor of cirrhosis in hepatitis C. To assess the role of CRS in predicting fibrosis progression in patients with initially no or minimal to moderate fibrosis, we investigated 271 untreated patients with chronic hepatitis C having initial liver biopsy showing METAVIR stage F0 (n = 104), F1 (n = 101), or F2 (n = 59) who had been followed up without antiviral therapies for at least 60 months (mean 108.5 +/- 71.5 months) and had a liver biopsy at the end of this observation period. Of these, 24.4% showed no histologic progression, 75.6% progressed by at least one stage, 45.0% progressed by at least two stages, and 10.3% progressed by more than two stages. The mean CRS was significantly higher (P = 0.005) in patients with fibrosis progression compared with those without progression, and this difference was particularly evident (P = 0.002) with F0 on initial biopsy. Mean CRS scores were not associated with degree of fibrosis progression. The relative risk of fibrosis progression increased with increasing CRS values. This association was significant in males but not in females and was most evident in males with F0 at initial biopsy (odds ratio 16.5, 95% confidence interval 1.6-166; P= 0.02) in the presence of high CRS. Multivariate analysis confirmed the significant association of CRS score with fibrosis progression. The predictive value of CRS was confirmed in hepatitis C virus patients admitting significant alcohol intake. CONCLUSION: Host genetics defined by CRS predict fibrosis progression in males with initially mild chronic hepatitis C and may become a useful parameter for prognostic evaluation and treatment decision.

SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C.

UNLABELLED: The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (> or =F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. CONCLUSION: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers.