A cross-sectional assessment of health-related quality of life in Chinese patients with chronic hepatitis c virus infection with EQ-5D.

BACKGROUND: Hepatitis C virus (HCV) infection is one of the most common liver infections, with a decrement in HRQoL of HCV patients. This study aims to assess Health-related quality of life (HRQoL) in Chinese patients with chronic HCV infection, and to identify significant predictors of the HRQoL in these patients of China. METHODS: In this cross-sectional observational study, treatment-naïve Han ethnic adults with chronic HCV infection were enrolled. Adopting European Quality of Life scale (EQ-5D) and EuroQOL visual analogue scale (EQ-VAS) were used to qualify HRQoL. Results were reported in descriptive analyses to describe sociodemographic and clinical characteristics. Multiple linear regression analysis was applied to investigate the associations of these variables with HRQoL. Binary logistic regression analysis was performed to identify associations of these variables with HRQoL by dimensions of EQ-5D. RESULTS: Nine hundred ninety-seven patients were enrolled in the study [median age 46.0 (37.0, 56.0) years; male 54.8%]. Mean EQ-5D index and EQ-VAS score were 0.780 ± 0.083 and 77.2 ± 14.8. Multiple Linear regression analysis showed that income (< 2000 RMB, ß = - 0.134; 2000-4999 RMB, ß = - 0.085), moderate or severe symptoms of discomfort (more than one symptoms, ß = - 0.090), disease profile (cirrhosis, ß = - 0.114), hyperlipidemia (ß = - 0.065) and depression (ß = - 0.065) were independently associated with EQ-5D index. Residence (the west, ß = 0.087), income (< 2000 RMB, ß = - 0.129; 2000-4999 RMB, ß = - 0.052), moderate or severe symptoms of discomfort (more than one symptoms, ß = - 0.091), disease profile and depression (ß = - 0.316) were the influencing factors on EQ-VAS. Binary logistic regression indicated that disease profile and clinical depression were the major influencing factors on all five dimensions of EQ-5D. CONCLUSIONS: In this cross-sectional assessment of HCV patients in China, we indicated HRQoL of Chinese HCV patients. Significant negative associations between HRQoL and sociodemographic and clinical factors such as moderate or severe symptoms of discomfort, disease profile and depression emerged. We have to focus on optimally managing care of HCV patients and improving their HRQoL. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01293279. Date of registration: February 10, 2011.

Comparison of ICD-9 Codes for Depression and Alcohol Misuse to Survey Instruments Suggests These Codes Should Be Used with Caution.

BACKGROUND: Research suggests depression and alcohol misuse are highly prevalent among chronic hepatitis C (CHC) patients, which is of clinical concern. AIMS: To compare ICD-9 codes for depression and alcohol misuse to validated survey instruments. METHODS: Among CHC patients, we assessed how well electronic ICD-9 codes for depression and alcohol misuse predicted these disorders using validated instruments. RESULTS: Of 4874 patients surveyed, 56% were male and 52% had a history of injection drug use. Based on the PHQ-8, the prevalence of depression was 30% compared to 14% based on ICD-9 codes within 12 months of survey, 37% from ICD-9 codes any time before or within 12 months after survey, and 48% from ICD-9 codes any time before or within 24 months after survey. ICD-9 codes predicting PHQ-8 depression had a sensitivity ranging from 59 to 88% and a specificity ranging from 33 to 65%. Based on the AUDIT-C, the prevalence of alcohol misuse was 21% compared to 3-23% using ICD-9 codes. The sensitivity of ICD-9 codes to predict AUDIT-C score ranged from 9 to 35% and specificity from 80 to 98%. Overall 39% of patients reported ever binge drinking, with a sensitivity of ICD-9 to predict binge drinking ranging from 7 to 33% and a specificity from 84 to 98%. More than half of patients had either an ICD-9 code for depression, a survey score indicating depression, or both (59%); more than one-third had the same patterns for alcohol misuse (36%). CONCLUSIONS: ICD-9 codes were limited in predicting current depression and alcohol misuse, suggesting that caution should be exercised when using ICD-9 codes to assess depression or alcohol misuse among CHC patients.

Treatment of Hepatitis C virus infection in Italy: A consensus report from an expert panel.

Hepatitis C virus (HCV) infection remains one of the main causes of chronic liver disease worldwide. The advent of direct-acting antivirals (DAAs) has significantly improved the course of patients with chronic HCV infection (CHC), due to the ability of these drugs to achieve high rates of sustained virological response (SVR). These exceedingly high rates of SVR and the excellent safety data have been confirmed in real life practice. Evolving guidelines have been issued by national and international scientific societies in accordance with the progression of clinical knowledge and the availability of new DAAs. These recommendations, however, may not be applied universally because of delays in drugs reimbursability in different countries and because some National Health Systems identify only patients with advanced disease as a treatment priority. Italy in this regard is a prototype about DAAs treatment of CHC patients. With the aim to assess the Italian treatment experience with DAAs and to respond to unmet needs in treatment optimization of antiviral therapy in specific settings of CHC patients, a group of Italian experts met in Stresa in February 2017. The summary of the considerations arising from this two-day meeting and some statements regarding a few open issues are reported in this position paper.

Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection.

BACKGROUND & AIMS: We conducted an open-label, randomized, phase 3 trial to determine the efficacy and safety of sofosbuvir and ribavirin, with and without peginterferon-alfa, in treatment-experienced patients with cirrhosis and hepatitis C virus (HCV) genotype 2 infection and treatment-naïve or treatment-experienced patients with HCV genotype 3 infection. METHODS: The study was conducted at 80 sites in Europe, North America, Australia, and New Zealand Patients were randomly assigned (1:1:1) to groups given sofosbuvir and ribavirin for 16 weeks (n = 196); sofosbuvir and ribavirin for 24 weeks (n = 199); or sofosbuvir, peginterferon-alfa, and ribavirin for 12 weeks (n = 197). The primary end point was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (sustained virologic response [SVR12]). From October 2013 until April 2014, we enrolled and treated 592 patients-48 with genotype 2 HCV and compensated cirrhosis who had not achieved SVR with previous treatments and 544 with genotype 3 HCV (279 treatment-naïve and 265 previously treated). Overall, 219 patients (37%) had compensated cirrhosis. The last post-treatment week 12 patient visit was in January 2015. RESULTS: Rates of SVR12 among patients with genotype 2 HCV were 87% and 100%, for those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 94% for those receiving sofosbuvir, peginterferon, and ribavirin for 12 weeks. Rates of SVR12 among patients with genotype 3 HCV were 71% and 84% in those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 93% in those receiving sofosbuvir, peginterferon, and ribavirin. On-treatment virologic failure occurred in 3 patients with HCV genotype 3a receiving sofosbuvir and ribavirin for 24 weeks. The most common adverse events were fatigue, headache, insomnia, and nausea. Overall, 1% of patients discontinued treatment due to adverse events. CONCLUSIONS: Among patients with genotype 3 HCV infection, including a large proportion of treatment-experienced patients with cirrhosis, the combination of sofosbuvir, peginterferon, and ribavirin for 12 weeks produces high rates of SVR. Treatment-experienced patients with cirrhosis and genotype 2 HCV infection had high rates of SVR in all groups. EudraCT ID 2013-002641-11.

Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes.

The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA

Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and transient elastography (FibroScan®).

BACKGROUND & AIMS: FibroTest™ (FT) and Transient Elastography (TE) have been validated as non-invasive markers of METAVIR fibrosis stages from F0 to F4 using biopsy, and as prognostic markers of liver related mortality in patients with chronic hepatitis C. The aim was to extend the validation of FT and TE as markers of critical steps defined by occurrence of cirrhosis without complications (F4.1), esophageal varices (F4.2), and severe complications (F4.3): primary liver cancer, variceal bleeding, or decompensation (ascites, encephalopathy, or jaundice). METHODS: The updated individual data of 3927 patients (1046 cirrhotics) without complications at baseline were pooled from three prospective cohorts called "EPIC", "Paris", and "Bordeaux" cohorts. RESULTS: At 5 years, among 501 patients without varices at baseline (F4.1) varices occurred in 19 patients [F4.2 incidence of 4.0% (95% CI 2.2-5.8)]. The predictive performance (AUROC) of FT was 0.77 (0.66-0.84; p<0.001). At 10 years severe complications occurred in 203 patients, [F4.3 incidence of 13.4% (9.6-17.1)], including primary liver cancer in 84 patients [6.4% (3.5-9.3)]. FT was predictive (Cox adjusted on treatment) of severe complications [AUROC 0.79 (76-82); p<0.0001], including primary liver cancer [AUROC 0.84 (80-87); p<0.0001]. Similarly TE was predictive of severe complications [AUROC 0.77 (72-81); p<0.0001], including primary liver cancer [AUROC 0.86 (81-90); p<0.0001]. CONCLUSIONS: FibroTest™ and TE increase were associated with the occurrence of all severe complications including hepatocellular carcinoma, hepatic insufficiency, and variceal bleeding. FibroTest™ increase was also associated with the occurrence of esophageal varices.

Chronic Hepatitis C treatment for genotype 2 or 3 in Brazil: cost effectiveness analysis of peginterferon plus ribavirin as first choice treatment

Brazilian Guidelines to HCV treatment (2007) recommended that the first choice treatment for patients with chronic hepatitis C (CHC) and genotype 2 or 3 is interferon alpha (IFN) plus ribavirin (RBV) for 24 weeks. The aim of this study is compare the cost and effectiveness to Hepatitis C treatment in patients with genotype 2 or 3 of peginterferon alpha (PEG) as the first choice of treatment within PEG for those that do not respond to IFN. The target population is CHC patients with genotype 2 or 3 in Brazil. The interventions are: PEG-SEC (first IFN plus RBV for 24 weeks, after, for non-responders and relapsers subsequently PEG plus RBV for 48 weeks); PEG-FIRST24 (PEG+RBV for 24 weeks). The type of the study is cost-effectiveness analysis. The data sources are: Effectiveness data from meta-analysis conducted on the Brazilian population. Treatment cost from Brazilian micro costing study is converted into USD (2010). The perspective is the Public Health System. The outcome measurements are Sustained Viral Response (SVR) and costs. PEG-FIRST24 (SVR: 87.8%, costs: USD 8,338.27) was more effective and more costly than PEG-SEC (SVR: 79.2%, costs: USD 5,852.99). The sensitivity analyses are: When SVR rates with IFN was less than 30% PEG-FIRST is dominant. On the other hand, when SVR with IFN was more then 75% PEG-SEC is dominant (SVR=88.2% and costs USD $ 3,753.00). PEG-SEC is also dominant when SVR to PEG24 weeks was less than 54%. In the Brazilian context, PEG-FIRST is more effective and more expensive than PEG-SEC. PEG-SEC could be dominant when rates of IFN therapy are higher than 75% or rates of PEG24 therapy are lower than 54%.

O protocolo brasileiro de tratamento da Hepatite C (2007) recomendava como primeira escolha para pacientes com hepatite C crônica e portadores de genótipo 2 ou 3 o tratamento com interferona alfa (IFN) associada à ribavirina (RBV), por 24 semanas. O objetivo deste estudo é comparar o custo e a efetividade para pacientes com hepatite C crônica e portadores do genótipo 2 ou 3 o uso de peguinterferon (PEG) como primeiro escolha com o PEG como secunda escolha para aqueles que não responderam ao tratamento com IFN. A população alvo compreende pacientes com hepatite C crônica portadores de genótipo 2 ou 3 no Brasil. As intervenções são: PEG-SEC (IFN + RBV por 24 semanas, para os não respondedores e recidivantes tratamento subsequente com PEG + RBV por 48 semanas; PEG-FIRST24 (PEG + RBV por 24 semanas). O tipo de estudo envolvido é Análise de Custo Efetividade. Os dados de efetividade são provenientes de um metanálise de estudos brasileiros e os dados de custo do tratamento de um estudo de custo do contexto brasileiro. A perspectiva é o Sistema Público de Saúde. Os desfechos avaliados foram Resposta Viral Sustentada (RVS) e Custos. PEG-FIRST24 (RVS: 87,8%, costs: USD 8.338,27) foi mais efetivo e apresentou maior custo que PEG-SEC (RVS: 79,2%, custo USD 5.852,99). A análise de sensibilidade demonstrou que PEG-SEC é dominado por PEG-FIRST24 quando RVS com IFN for menor que 30%. Por outro lado, quando RVS com IFN for maior que 75% PEG-SEC é dominante (RVS=88.2% e custo USD $ 3.753,00). PEG-SEC é também dominante quando RVS para PEG24 for menor que 54%. Conclusão: No contexto brasileiro, PEG-FIRST é mais efetivo e mais custoso que PEG-SEC. PEG-SEC poderia ser dominante quando as taxas de RVS do tratamento com IFN forem superiores a 75% ou as taxas de PEG24 forem inferiores a 54%.

[Chronic liver diseases--new therapy. Are biopsies necessary?]. / Chronische Lebererkrankungen--neue Therapie. Benötigen wir die Biopsie?

Chronic liver disease can often reliably be assessed only by examination of biopsy material. In this article the possible indications for liver biopsy in viral hepatitis B and C, autoimmune liver disease, steatohepatitis and hereditary metabolic diseases are described. A biopsy may be useful in cases with unclear clinical or serological situations or with questionable chronicity and comorbidities. The assessment of biopsy material should be based on guideline-based classification systems. The value of biopsy diagnosis benefits from a close interdisciplinary clinical pathological cooperation.

[Predicting side effects of the treatment of chronic hepatitis with peginterferon alpha-2A with ribaverin].

The aim of the study was to monitor the commonest side effects of the treatment of chronic hepatitis with peginterferon alpha-2A (PEG-IFN) and ribaverin (RBV) and the influence of various factors on their development. The work was done in the Department of Infectious Disease, Erevan State Medical University. Monitoring 16 adverse reactions was carried out with the use of special tables within 1, 2, 4 and 6 months after the onset of therapy in patients with genotypes 2 and 3 and in addition after 8, 10 and 12 months in patients with genotype 1. The influence of independent prognostic factors was estimated by logistic regression analysis. The commonest side effects of PEG-IFN plus RBV therapy were leukopenia, thrombocytopenia, weight loss, depression, fatigue, and insomnia that occurred at one time or another in more than half of the patients. Weight loss during therapy amounted to 8.36 kg (95% CI 6.7-10) (maximum 21 kg). Myalgia, anorexia, arthralgia, headache, alopecia, and vomiting were documented in 20-50% of the cases. Anemia, pruritis, eruption, erythema, and hair shedding at injection sites occurred in 1/4 of the patients. It is concluded that logistic regression analysis with matching selected prognostic factors permits to estimate the probability of such side effects as weight loss, flu-like syndrome, and myalgia.

Poly-ε -caprolactone microspheres containing interferon alpha as alternative formulations for the treatment of chronic hepatitis C

Interferon-alpha (IFN-alpha) is one of the main drugs used in the treatment of hepatitis C. Use of IFN-alpha has some limitations that result in poor treatment efficacy and low patient compliance. Therefore, the aim of this study was to develop poly-ε-caprolactone (PCL) microspheres containing IFN-alpha as an alternative for the treatment of chronic hepatitis C. Microspheres were prepared using the multiple emulsion followed by solvent evaporation technique. Particle size, surface morphology, drug content and encapsulation efficiency of the microspheres produced were evaluated. The stability of the formulation was assessed after 90 days at -20ºC. An in vitro release study was performed in PBS. In vitro cytotoxicity of the formulation was studied using hepatic cell line. The freeze-dried microspheres had mean particle size, IFN-alpha content, and encapsulation efficiency of 38.52 ± 4.64 µm, 15.52 ± 3.28% and 83.93 ± 5.76%, respectively. There were no significant changes during storage and the structural integrity of the protein was not compromised by the preparation technique. A total of 82% of the IFN-alpha was released after 28 days and the developed microspheres did not present cytotoxicity to the hepatic cell line. In vivo studies are currently underway to evaluate the biological activity of IFN-alpha encapsulated into microspheres.

O interferon alfa (IFN-alfa) é um dos principais fármacos utilizados no tratamento de hepatite C, mas o seu uso apresenta limitações que resultam em baixa eficácia do tratamento e não adesão do paciente. Diante disso, este estudo objetiva o desenvolvimento de microesferas de poli-ε-caprolactona (PCL) contendo IFN-alfa como alternativa ao tratamento de hepatite C crônica. As microesferas foram preparadas pelo método de emulsão múltipla seguido de evaporação do solvente e caracterizadas quanto ao diâmetro médio das partículas, morfologia da superfície, taxa e eficiência de encapsulamento. A estabilidade da formulação foi acompanhada durante 90 dias a -20 ºC. O estudo de liberação in vitro foi realizado em PBS. A citotoxicidade da formulação foi avaliada utilizando linhagem de células hepáticas. As microesferas liofilizadas apresentaram diâmetro médio, taxa de encapsulamento e eficiência de encapsulamento de 38,52 ± 4,64 µm, 15,52 ± 3,28% e 83,93 ± 5,76%, respectivamente. Não foram observadas alterações significativas durante o armazenamento e a integridade estrutural da proteína foi mantida após o preparo. Oitenta e dois por cento de IFN-alfa foram liberados em 28 dias e a formulação desenvolvida não apresentou toxicidade para as células testadas. Estudos in vivo estão em andamento para avaliar a atividade biológica do IFN-alfa encapsulado nas microesferas.

Analysis of the PKR-eIF2alpha phosphorylation homology domain (PePHD) of hepatitis C virus genotype 1 in HIV-coinfected patients by ultra-deep pyrosequencing and its relationship to responses to pegylated interferon-ribavirin treatment.

Chronic coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is among the greatest challenges facing public health worldwide. In this population, the response to hepatitis C therapy by treatment with pegylated interferon plus ribavirin (PEG-IFN+RBV) is lower than in HCV-monoinfected patients, particularly in those infected by HCV genotype 1. A PKR/eIF-2α phosphorylation homology domain (PePHD) within the E2 protein has been found to interact with PKR and inhibit PKR in vitro, suggesting a possible mechanism for HCV to evade the antiviral effects of IFN. The aim of this work was to analyze the amino acid conservation in the HCV-E2-PePHD and quasispecies diversity among HCV-HIV-coinfected patients exhibiting sustained virological response, non-response, or partial response with viral relapse to PEG-IFN+RBV by ultra-deep pyrosequencing. For this purpose, HCV-E2-PePHD PCR products were generated and sequenced directly for four patients with a sustained response, seven patients with no virological response, and four patients with viral relapse before and after treatment with PEG-IFN+RBV. HCV-E2-PePHD amino acid sequences were obtained for isolates from serum collected before and during treatment (24 h, 4 weeks, and 12 weeks). Quasispecies analysis of the HCV-E2-PePHD and flanking genomic regions was performed using 454/Roche pyrosequencing, analyzing 39,364 sequence reads in total. The HCV-E2-PePHD sequence at the amino acid and nucleotide level was highly conserved among HCV genotype 1 strains, irrespective of the PEG-IFN+RBV response. This high degree of amino acid conservation and sporadic mutations in the HCV-E2-PePHD domain do not appear to be associated with treatment outcome. The HCV-E2-PePHD sequence before or during treatment cannot be used to predict reliably the outcome of treatment in patients coinfected with HCV genotype 1 and HIV.

Comparison of eight diagnostic algorithms for liver fibrosis in hepatitis C: new algorithms are more precise and entirely noninvasive.

UNLABELLED: The sequential algorithm for fibrosis evaluation (SAFE) and the Bordeaux algorithm (BA), which cross-check FibroTest with the aspartate aminotransferase-to-platelet ratio index (APRI) or FibroScan, are very accurate but provide only a binary diagnosis of significant fibrosis (SAFE or BA for Metavir F ≥ 2) or cirrhosis (SAFE or BA for F4). Therefore, in clinical practice, physicians have to apply the algorithm for F ≥ 2, and then, when needed, the algorithm for F4 ("successive algorithms"). We aimed to evaluate successive SAFE, successive BA, and a new, noninvasive, detailed classification of fibrosis. The study included 1785 patients with chronic hepatitis C, liver biopsy, blood fibrosis tests, and FibroScan (the latter in 729 patients). The most accurate synchronous combination of FibroScan with a blood test (FibroMeter) provided a new detailed (six classes) classification (FM+FS). Successive SAFE had a significantly (P < 10(-3) ) lower diagnostic accuracy (87.3%) than individual SAFE for F ≥ 2 (94.6%) or SAFE for F4 (89.5%), and required significantly more biopsies (70.8% versus 64.0% or 6.4%, respectively, P < 10(-3) ). Similarly, successive BA had significantly (P ≤ 10(-3) ) lower diagnostic accuracy (84.7%) than individual BA for F ≥ 2 (88.3%) or BA for F4 (94.2%), and required significantly more biopsies (49.8% versus 34.6% or 24.6%, respectively, P < 10(-3) ). The diagnostic accuracy of the FM+FS classification (86.7%) was not significantly different from those of successive SAFE or BA. However, this new classification required no biopsy. CONCLUSION: SAFE and BA for significant fibrosis or cirrhosis are very accurate. However, their successive use induces a significant decrease in diagnostic accuracy and a significant increase in required liver biopsy. A new fibrosis classification that synchronously combines two fibrosis tests was as accurate as successive SAFE or BA, while providing an entirely noninvasive (0% liver biopsy) and more precise (six versus two or three fibrosis classes) fibrosis diagnosis.

Comparison of accuracy of fibrosis degree classifications by liver biopsy and non-invasive tests in chronic hepatitis C.

BACKGROUND: Non-invasive tests have been constructed and evaluated mainly for binary diagnoses such as significant fibrosis. Recently, detailed fibrosis classifications for several non-invasive tests have been developed, but their accuracy has not been thoroughly evaluated in comparison to liver biopsy, especially in clinical practice and for Fibroscan. Therefore, the main aim of the present study was to evaluate the accuracy of detailed fibrosis classifications available for non-invasive tests and liver biopsy. The secondary aim was to validate these accuracies in independent populations. METHODS: Four HCV populations provided 2,068 patients with liver biopsy, four different pathologist skill-levels and non-invasive tests. Results were expressed as percentages of correctly classified patients. RESULTS: In population #1 including 205 patients and comparing liver biopsy (reference: consensus reading by two experts) and blood tests, Metavir fibrosis (FM) stage accuracy was 64.4% in local pathologists vs. 82.2% (p < 10-3) in single expert pathologist. Significant discrepancy (≥ 2FM vs reference histological result) rates were: Fibrotest: 17.2%, FibroMeter2G: 5.6%, local pathologists: 4.9%, FibroMeter3G: 0.5%, expert pathologist: 0% (p < 10-3). In population #2 including 1,056 patients and comparing blood tests, the discrepancy scores, taking into account the error magnitude, of detailed fibrosis classification were significantly different between FibroMeter2G (0.30 ± 0.55) and FibroMeter3G (0.14 ± 0.37, p < 10-3) or Fibrotest (0.84 ± 0.80, p < 10-3). In population #3 (and #4) including 458 (359) patients and comparing blood tests and Fibroscan, accuracies of detailed fibrosis classification were, respectively: Fibrotest: 42.5% (33.5%), Fibroscan: 64.9% (50.7%), FibroMeter2G: 68.7% (68.2%), FibroMeter3G: 77.1% (83.4%), p < 10-3 (p < 10-3). Significant discrepancy (≥ 2 FM) rates were, respectively: Fibrotest: 21.3% (22.2%), Fibroscan: 12.9% (12.3%), FibroMeter2G: 5.7% (6.0%), FibroMeter3G: 0.9% (0.9%), p < 10-3 (p < 10-3). CONCLUSIONS: The accuracy in detailed fibrosis classification of the best-performing blood test outperforms liver biopsy read by a local pathologist, i.e., in clinical practice; however, the classification precision is apparently lesser. This detailed classification accuracy is much lower than that of significant fibrosis with Fibroscan and even Fibrotest but higher with FibroMeter3G. FibroMeter classification accuracy was significantly higher than those of other non-invasive tests. Finally, for hepatitis C evaluation in clinical practice, fibrosis degree can be evaluated using an accurate blood test.

Editorial: staging liver fibrosis in hepatitis C: a challenge for this decade.

The limitations of and the invasive nature of liver biopsy has spurred extensive interest in the development of non-invasive tests to measure liver fibrosis in patients with chronic hepatitis C. Clinically applicable non-invasive tests, including radiological studies, elastography, and serum markers, all of which perform extremely well in excluding significant disease and diagnosing cirrhosis. FibroScan and acoustic radiation force impulse elastography are two elastography-based tests that show promise. In this new era of increased cure rates with newly Food and Drug Administration-approved drugs and the availability of multiple non-invasive tests of liver fibrosis, we anticipate a decreasing need for liver biopsies in the management of chronic hepatitis C.

Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C.

OBJECTIVES: Transient elastography (TE) is adequate for a diagnosis of cirrhosis, but its accuracy for milder stages of fibrosis is much less satisfactory. The objective of this study was to compare the performance and the discordance rate of acoustic radiation force impulse (ARFI) and TE with liver biopsy in a cohort of chronic hepatitis C (CHC) patients. METHODS: One hundred thirty-nine consecutive patients with CHC were enrolled in two tertiary centers, and evaluated for histological (Metavir score) and biochemical features. All patients underwent TE and ARFI. RESULTS: TE was unreliable in nine patients (6.5%), while in no cases (0%) were ARFI invalid measurements recorded (P=0.029). By area under receiver operating characteristic curve (AUROC), the best cutoff values for TE and ARFI for significant fibrosis (≥F2) were ≥6.5 kPa (AUROC: 0.78) and ≥1.3 m/s (AUROC: 0.86), respectively. For severe fibrosis (F3-F4), these cutoff values were 8.8 kPa (AUROC: 0.83) for TE and 1.7 m/s (AUROC: 0.94) for ARFI. For cirrhosis, TE had its best cutoff at ≥11 kPa (AUROC: 0.80) and ARFI at ≥2.0 m/s (AUROC: 0.89). By pairwise comparison of AUROC, ARFI was significantly more accurate than TE for a diagnosis of significant and severe fibrosis (P=0.024 and P=0.002, respectively), while this difference was only marginal for cirrhosis (P=0.09). By partial AUROC analysis, ARFI performance results significantly higher for all three stages of fibrosis. The average concordance rates of TE and ARFI vs. liver biopsy were 45.4 and 54.7%, respectively. By multivariate analysis, ARFI was not associated with alanine aminotransferase (ALT), body mass index, Metavir grade, and liver steatosis, while TE was significantly correlated with the ALT value (P=0.027). CONCLUSIONS: In a cohort of patients with CHC, ARFI imaging was more accurate than TE for the non-invasive staging of both significant and severe classes of liver fibrosis.

Evaluation of chronic HCV infection in transplanted livers using a modified histological activity index.

BACKGROUND: The majority of histopathological classifications of primary chronic viral hepatitis and recurrence of HCV infection in liver transplants is based on the histological activity index (HAI) introduced by Knodell et al in 1981; however, correlation between HAI and clinical/laboratory data is poor. Therefore, the aim of this study was to present a modification of HAI (mHAI) adapted to distinct features of graft infection, and to evaluate its usefulness in the description of disease activity. MATERIAL/METHODS: Inflammatory activity in 67 biopsies of HCV-infected grafted livers was semi-quantitatively assessed according to HAI based on Knodell's criteria and to mHAI proposed by the authors. Patients were divided into 4 groups according to level of clinical aggressiveness of HCV reinfection on the basis of laboratory data. Correlations between clinical aggressiveness and histological activity of the disease expressed as HAI or mHAI was estimated. RESULTS: Histological features of HCV reinfection of various activity were observed as early as in the second month after orthotopic liver transplantation. HAI and mHAI values were similar in 55.2% of cases, but in 38.8% HAI was lower than mHAI. Morphological and clinical features were found to be consistent in 32.8% and 49.3% of cases for HAI and mHAI evaluation, respectively. mHAI seems to correlate with clinical assessment of HCV recurrence in liver grafts significantly better than does the classical HAI. CONCLUSIONS: mHAI proposed in the present study appears to be more useful for evaluation of recurrence of HCV infection in post-transplant liver biopsies.

Role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver disease.

BACKGROUND & AIMS: Fibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients with mild liver fibrosis. In addition, we evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test. METHODS: Two separate cohorts of HCV patients (Brussels, Belgium/Hannover, Germany) were retrospectively analyzed. Only patients with a fibrosis Ishak or METAVIR score of F0-F1 at baseline were included. Patients were classified as progressors if they showed an increase ≥2 fibrosis stages at the second histological evaluation after a follow-up ≥5years. The CRS was calculated locally. Genotyping was performed by PCR and oligonucleotide ligation with the resulting signal detected with a Luminex® 200TM and computer analysis. RESULTS: In Brussels, 12/25 patients progressed (48%); similarly in Hannover, 16/31 (52%) patients progressed. In both sample sets, the CRS was significantly associated with fibrosis progression (p=0.050 in Brussels; p=0.018 in Hannover). The ELF test was only a significant predictor in Hannover (p=0.015). In multivariate analysis the CRS remained the only variable associated with fibrosis progression (odds-ratio=2.23, 95%CI 1.21-4.11 p=0.01). CONCLUSIONS: Although conducted on a limited number of patients, this study in two independent centres confirms that the CRS predicts fibrosis progression in initially mild CHC.

Noninvasive assessment of liver fibrosis with acoustic radiation force impulse imaging: increased liver and splenic stiffness in patients with liver fibrosis and cirrhosis.

PURPOSE: To evaluate acoustic radiation force impulse imaging (ARFI) of the liver and spleen as a new method for the noninvasive assessment of liver fibrosis (LF). MATERIALS AND METHODS: Three groups of 58 examinees were studied: (A) 20 healthy volunteers; (B) 18 patients with chronic viral hepatitis (CVH) B or C having liver fibrosis stages F 1 - 4 (assessed by liver biopsy; Ishak classification); and (C) 20 patients with liver cirrhosis (LC). All participants were examined using the Siemens ACUSON S 2000 Ultrasound Virtual Touch Tissue Quantification system. Ten measurements were performed on both liver lobes and three measurements on the spleen, and the obtained mean values (shear wave velocities [SWV] expressed in m/s) were compared between the groups. In 20 patients the splenic artery pulsatility index (SAPI) was also measured and correlated to the liver and splenic ARFI and histological stage of LF. RESULTS: Hepatic ARFI measurements demonstrated a significant correlation to LB results (Spearman's ρ = 0.766; ρ < 0.001) and SWV cut-off values of 1.3 (AUC 0.96) and 1.86 (AUC 0.99) could reliably differentiate between healthy (A) and non-cirrhotic CVH (B), as well as between non-cirrhotic CVH (B) and LC (C). Splenic SWV cut-off value of 2.73 (AUC 0.82) could differentiate between the patients with LC and non-cirrhotic CVH. A significant correlation was also observed between the SAPI and liver ARFI results (ρ = 0.56; p = 0.013). CONCLUSION: The hepatic and splenic SWV measured by ARFI increase with the LF stage, and the hepatic SWV correlate well with SAPI. This new technology enables simultaneous morphological, Doppler and elastometric examinations and might improve the accuracy of noninvasive liver fibrosis assessment.

Evaluation of ocular surface damage and dry eye status in chronic hepatitis C at different stages of hepatic fibrosis.

PURPOSE: The purpose of this study was to explore changes in ocular surface and tear function parameters in chronic hepatitis C at different stages of hepatic fibrosis. METHODS: Fifty-four patients with biopsy-proven chronic hepatitis C and 54 age- and sex-matched healthy control subjects without systemic hepatitis C infection were examined with the Ocular Surface Disease Index questionnaire, Schirmer with and without anesthesia, tear film breakup time, and scoring of ocular surface Lissamine green staining using modified Oxford and van Bijsterveld scoring systems and corneal fluorescein staining. RESULTS: Patients with chronic hepatitis C scored significantly worse than the control subjects on all parameters: modified Oxford scores of Lissamine green staining (5.5/3.0; P <0.001), Oxford and van Bijsterveld scores (4.0/2.0; P <0.001), and corneal fluorescein staining (1.5/0.0; P = 0.001). The chronic hepatitis C group also had higher Ocular Surface Disease Index scores than the control subjects (22.3/13.7; P = 0.001). Schirmer with and without anesthesia and tear film breakup time scores were found to be lower in patients with chronic hepatitis C (P <0.001). Moreover, patients with advanced stages of hepatic fibrosis (stages 4-6) had significantly lower values of tear film breakup time and worse Ocular Surface Disease Index scores and ocular surface vital dye staining than those with initial stages of hepatic fibrosis (stages 0-3). CONCLUSION: Patients with chronic hepatitis C, especially those with advanced stages of hepatic fibrosis, were more likely to exhibit severe ocular surface damage and signs of dry eye.