F4 Patients Research Articles

1529-P: Higher Rates of Disease Progression among Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) Patients with Advanced Fibrosis (AF) and Diabetes Mellitus (DM)

Objective: Prevalence of NAFLD/NASH is high in DM patients. Presence of DM has been suggested to potentially accelerate liver disease progression among these patients. The study aimed to assess the adverse events among NAFLD/NASH patients with AF (F3 and compensated cirrhosis/F4) stratified by DM status. Methods: Adult NAFLD/NASH-AF patients with available lab results were identified from Optum Research claims data (2008-2016), to calculate their Fibrosis-4 (FIB-4) scores. Using the score, patients were categorized as F3 or F4 (first date of cut-off score as index date), and then stratified by DM. Events were measured as first date of FIB-4 score/diagnosis consistent with F4, or presence of decompensated cirrhosis (DCC) after initial diagnosis of NAFLD/NASH with F3 or F4. Results: Among 91,122 NAFLD/NASH patients with FIB-4 scores, 2,482 (2.7%) had F3 and 939 (1.0%) had F4 stage of fibrosis. 36% of F3 and 35% of F4 patients had DM. Overall, incident event rates for patients with NAFLD/NASH - F3 and F4 with DM were higher than those without DM (Figure). Incident DCC rates were also higher in NAFLD/NASH with DM [F3 (33.9%) (p=0.19) and F4 (70.1%) (p=0.04)] than without DM. Conclusions: NAFLD/NASH patients with AF and DM have higher rates of adverse events. These patients must be identified early for close monitoring and management. Disclosure Z. Younossi: Consultant; Self; Gilead Sciences, Inc. N. Kachru: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. S. Shreay: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. R. Loomba: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc.

Clinical validation of ultrasound backscatter statistics for the assessment of liver fibrosis

Introduction Deposition of fibrous tissue in the liver changes with the progression of liver cirrhosis. Ultrasound backscatter imaging may describe the scatterer distribution in the liver, and reflect the severity of liver cirrhosis. However, it is known that the backscatter statistics are often subject to ultrasound imaging settings, region of interest (ROI) for analysis and hepatic steatosis. This study aims to establish a standard imaging procedure and a discriminant model for assessment of liver fibrosis regardless of the degrees of liver fatty changes. Methods 201 patients received elective liver resection were prospectively enrolled in the study. Ultrasound radio-frequency (RF) data of right liver lobe through an intercostal space with the maximum imaging depth of 8cm were collected using the Terason t3000 ™ (convex array) system pre-operatively from each patient. Since significant inter-ROI variation was found when the ROI is less than 10 cm2, all the ROI's were selected such that the ROI area covered as much as possible the liver parenchyma and was larger than 10 cm2. The liver tissue was examined and determined by an experienced pathologist the degrees of liver fibrosis and fatty changes. Among the 201 patients, there were 36 F0, 51 F1, 26 F2, 22 F3 and 66 F4 patients while 62 with mild steatosis (5-30%) and 26 with severe steatosis (> 30%). A FDA-cleared backscatter analysis tool (AmCAD-USTM) was used to calculate the statistics and a stepwise logistic regression model was established to differentiate significant liver fibrosis (≥ F2). Results Three backscatter statistics, including the 95th percentile of the Nakagami (m) statistic, and the 75th and 95th percentiles of the histogram (h) statistics, were selected into the logistic model. Regardless of the liver fatty changes, the Receiver Operating Characteristic (ROC) curve analysis showed a significant discriminant power of the model for evaluation of liver fibrosis - stage 0 versus stage 1-4, AUC 0.77 (p-value Conclusions The liver fibrosis in human results in variation of the scatterer distributions in medical ultrasound imaging. Following a standard imaging procedure, a discriminant model is established and shown to be able to distinguish significantly different degrees of liver fibrosis regardless of the presence of steatosis.

Liver fibrosis staging with combination of APRI and FIB-4 scoring systems in chronic hepatitis C as an alternative to transient elastography.

Background:Liver disease severity must be determined before treatment of chronic hepatitis C (CHC). We evaluated the diagnostic performance of the APRI and FIB-4 scores compared to transient elastography liver stiffness (TE-LS) in detecting significant fibrosis (F3) or cirrhosis (F4).Methods:We retrospectively enrolled 575 patients with CHC who underwent TE-LS between May 2014 and September 2018: 365 (63.5%) male, mean age 51.54±12.4 years. APRI and FIB-4 scores were compared to TE-LS.Results :One hundred patients (17.5%) had TE-LS values between 9 and 11.9 kPa, and were classified as F3, while 265 (46%) were classified as F4 (TE-LS ≥12 kPa). APRI and FIB-4 scores predicted F4 patients adequately using cutoff values of 0.65 (sensitivity 85.5%, specificity 77%) and 1.63 (sensitivity 91%, specificity 77%), respectively. Cutoff values of 0.64 for APRI and 1.46 for FIB-4 predicted F3/F4 patients (sensitivity 72% and 81.5%; specificity 83% and 79%, respectively). The use of these cutoff values with APRI and FIB-4 in combination adequately predicted patients with significant fibrosis or cirrhosis (positive predictive value 91.5%), while cutoff values of 0.3 and 0.98, respectively, predicted F1/F2 patients with specificity 94.5% and sensitivity 26.5%, suggesting that in 58.5% of patients TE-LS could possibly be avoided.Conclusions:The APRI/FIB-4 combination performed well in predicting significant fibrosis, while FIB-4 performed well in predicting cirrhosis. These noninvasive biochemical markers could be used as screening tools instead of LS measurement, which is not widely available. Further prospective validation studies are required to confirm this finding.

Correction: Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications.

[This corrects the article DOI: 10.1371/journal.pone.0197117.].

Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications.

Background and aimsAdvanced liver fibrosis is an important predictor of liver disease progression and mortality, and current guidelines recommend screening for complications of cirrhosis once patients develop F3 fibrosis. Our study compared liver disease progression and survival in patients with stage 3 (F3) and stage 4 (F4) fibrosis on liver biopsy.MethodsRetrospective study of patients with F3 or F4 on liver biopsy followed for development of liver disease complications (variceal bleeding, ascites, and hepatic encephalopathy); hepatocellular carcinoma, and survival (overall and transplant free survival).ResultsOf 2488 patients receiving liver biopsy between 01/02 and 12/12, a total of 294 (171 F3) were analyzed. Over a median follow up period of 3 years, patients with F4 (mean age 53 years, 63% male) compared to F3 (mean age 49 years, 43% male) had higher five year cumulative probability of any decompensation (38% vs. 14%, p<0.0001), including variceal bleed (10% vs. 4%, p = 0.014), ascites (21% vs. 9%, p = 0.0014), and hepatic encephalopathy (14% vs. 5%, p = 0.003). F4 patients also had lower overall 5-year survival (80% vs. 93%, p = 0.003) and transplant free survival (80% vs. 93%, p = 0.002). Probability of hepatocellular carcinoma in 5 years after biopsy was similar between F3 and F4 (1.2% vs. 2%, p = 0.54).ConclusionsCompared to F4 stage, patients with F3 fibrosis have decreased risk for development of liver disease complications and better survival. Prospective well designed studies are suggested with large sample size and overcoming the limitations identified in this study, to confirm and validate these findings, as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.

Impact of hepatitis C virus genotype-4 eradication following direct acting antivirals on liver stiffness measurement.

BackgroundLiver fibrosis is the most important prognostic factor in chronic hepatitis C virus (HCV) patients, and Egypt shows the highest worldwide HCV prevalence with genotype-4 pre-dominance. The aim of this study was to investigate the degree of liver stiffness measurement (LSM) improvement after successful HCV eradication.Patients and methodsThe study included 84 chronic HCV Egyptian patients, and was conducted at Qena University Hospital from November 1, 2015 till October 31, 2016. LSM was obtained by FibroScan® before starting direct acting antiviral (DAA) treatment and after achieving sustained virologic response-24 (SVR-24). Based on baseline LSM, patients were stratified into F0–F1, F2, F3 and F4 groups (METAVIR). LSM and laboratory data after achieving SVR-24 was compared with that before starting therapy in each fibrosis group (F0-F4), p-value <0.05 was statistically significant.ResultsFollowing DAA treatment, 80 patients achieved SVR-24; of these, 50 were males (62.5%), mean age: 54.2±7.6 years, and mean body mass index: 28.6±2.2 kg/m2. Mean baseline LSM dropped from 15.6±10.8 to 12.1±8.7 kPa post-SVR; the maximum change of −5.8 occurred in F4 versus −2.79, −1.28 and +0.08 in F3, F2 and F0–F1 respectively (p<0.0001). At baseline, 41 patients were in the F4 group; only 16 (39%) regressed to non-cirrhotic range (<12.5 kPa), while 25 (61%) were still cirrhotic despite achieving SVR-24 (p<0.0001). Patients who achieved LSM improvement (n=64) have had significantly higher baseline aspartate transferase (AST) and alanine transaminase (ALT). Also, those patients showed significant improvement in AST, AST/platelets ratio index (APRI) and fibrosis-4 index (Fib-4) after achieving SVR; 91% showed AST improvement (p=0.01) and APRI improvement (p=0.01) and 81% showed Fib-4 improvement (p=0.04). Females, diabetics, patients with S3 steatosis and patients older than 50 years showed less LSM improvements than their counterparts. Baseline LSM ≥9 kPa, bilirubin ≥1 mg/dl, ALT ≥36 U/L and AST ≥31 U/L were significant predictors for LSM improvement.ConclusionSuccessful HCV genotype-4 eradication results in significant LSM improvement; the best improvement occurs in F4 patients. But as the majority of cirrhotics are still at risk for liver decompensation and hepatocellular carcinoma development despite achieving SVR-24, early detection and treatment are highly recommended.

Direct-acting antivirals combination for elderly patients with chronic hepatitis C: A cost-effectiveness analysis.

Chronic hepatitis C (CHC) has been undertreated among elderly patients. Interferon-free treatment represents an opportunity for these patients. The aim of this study was to assess the cost-effectiveness of directly acting antivirals (DAAs) in CHC elderly patients. A Markov model of CHC natural history was built. This study focuses on CHC patients older than 65years, stratified according to genotype (1/4, 2 and 3), liver fibrosis (METAVIR F1 to F4), age and frailty phenotype (robust, pre-frail and frail). DAAs combination vs no treatment was simulated for each theoretical population, assessing life years, quality-adjusted life years (QALYs), costs, incremental cost-effectiveness ratios (ICERs) in a lifetime time horizon and by the Healthcare System perspective. Incremental cost-effectiveness ratio increased with age and frailty status in all fibrosis stages. For robust F3 and F4 patients ICERs remained below the willingness-to-pay threshold (WTP) of 40000€/QALY up to age 75 and 86years, respectively, depending on drug price and sustained virological response probability (sensitivity analysis). Notably, in F4 and frail subjects older than 75years, ICER was more sensitive to non-liver-related mortality rate. In elderly F1 and F2 patients, ICERs were below WTP only up to 77years old, with wide variability among frailty phenotypes. Cost-effectiveness of DAAs treatment of elderly CHC patients is solid in those with advanced fibrosis, but it depends strongly on frailty status and age, particularly in patients with milder fibrosis stages. Accurate assessment of clinical variables, including frailty, is necessary to allocate limited resources to this special population.

Sustained Virologic Response Predicts Fibrosis Regression Measured by FibroTest in HCV-infected Patients

Introduction: Sustained virologic response (SVR) after treatment of chronic hepatitis C virus (HCV) reduces the risk for fibrosis progression. The 3 direct-acting antiviral regimen of ombitasvir (OBV), paritaprevir (identified by AbbVie and Enanta, co-dosed with ritonavir [PTV/r]), and dasabuvir (DSV) with or without ribavirin (RBV) has shown high SVR rates in HCV genotype (GT) 1 infected patients with or without cirrhosis. We assessed factors predictive of improvements in fibrosis from baseline as measured by FibroTest. Methods: TURQUOISE-II (GT1 with compensated cirrhosis) and TOPAZ-II (GT1 with or without compensated cirrhosis) patients treated with OBV/PTV/r + DSV ± RBV for 12 or 24 weeks,with FibroTest scores at baseline and at least one post-treatment week (PTW) visit were included. Stepwise logistic regression assessed the relative contribution of baseline factors, including fibrosis stage, sex, age, BMI, achievement of SVR, prior HCV treatment status, platelet count, ALT, and albumin on improvement from baseline in FibroTest score. FibroTest-derived fibrosis stage change from baseline was evaluated. The upper thresholds for METAVIR F0-1, F2, and F3 were 0.48, 0.58, and 0.72, respectively. Results: FibroTest scores at baseline and at one post-treatment visit were available for 882 patients, of whom 413 (47%) had F4 baseline METAVIR scores. For patients with PTW12 data, fibrosis stage regression occurred in 197/396 (50%) F4 patients, 73/114 (64%) F3 patients, 59/86 (69%) F2 patients, and was stable in 250/260 (96%) F0-1 patients (Table). In patients achieving SVR subgrouped by baseline METAVIR score, FibroTest least square mean changes from baseline were significantly different from no change. These changes were statistically different from those in patients that did not achieve SVR (F4: -0.17 vs -0.11; F3: -0.15 vs +0.05; F2: -0.13 vs +0.23; F0-1: -0.05 vs +0.07 for SVRs vs non-SVRs respectively). Achievement of SVR was strongly associated with FibroTest score improvement and patients with BL F4 fibrosis were more likely to have improvement than patients with F0-1, though not compared to patients with F2 or F3 fibrosis. Conclusion: Improvements in mean FibroTest score were observed in patients treated with OBV/PTV/r + DSV ± RBV and achieving SVR, irrespective of baseline score. Achievement of SVR was a predictor of improvement in FibroTest score and led to FibroTest-derived fibrosis stage regression for the majority with baseline F2 - F4 fibrosis.Table 1: Cross-Tabulation of Number and Proportion of Patients by Baseline and PTW12 FibroTest-Derived METAVIR Scores, n (%)

Estimating the clinical and economic benefit associated with incremental improvements in sustained virologic response in chronic hepatitis C.

IntroductionHepatitis C virus (HCV) infection is one of the principle causes of chronic liver disease. Successful treatment significantly decreases the risk of hepatic morbidity and mortality. Current standard of care achieves sustained virologic response (SVR) rates of 40–80%; however, the HCV therapy landscape is rapidly evolving. The objective of this study was to quantify the clinical and economic benefit associated with increasing levels of SVR.MethodsA published Markov model (MONARCH) that simulates the natural history of hepatitis C over a lifetime horizon was used. Discounted and non-discounted life-years (LYs), quality-adjusted life-years (QALYs) and cost of complication management were estimated for various plausible SVR rates. To demonstrate the robustness of projections obtained, the model was validated to ten UK-specific HCV studies.ResultsQALY estimates ranged from 18.0 years for those treated successfully in fibrosis stage F0 to 7.5 years (discounted) for patients in fibrosis stage F4 who remain untreated. Predicted QALY gains per 10% improvement in SVR ranged from 0.23 (F0) to 0.64 (F4) and 0.58 (F0) to 1.35 (F4) in 40 year old patients (discounted and non-discounted results respectively). In those aged 40, projected discounted HCV-related costs are minimised with successful treatment in F0/F1 (at approximately £300), increasing to £49,300 in F4 patients who remain untreated. Validation of the model to published UK cost-effectiveness studies produce R2 goodness of fit statistics of 0.988, 0.978 and of 0.973 for total costs, QALYs and incremental cost effectiveness ratios, respectively.ConclusionProjecting the long-term clinical and economic consequences associated with chronic hepatitis C is a necessary requirement for the evaluation of new treatments. The principle analysis demonstrates the significant impact on expected costs, LYs and QALYs associated with increasing SVR. A validation analysis demonstrated the robustness of the results reported.

Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis.

To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-naïve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P ≤ 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR.

The future disease burden of hepatitis C virus infection in Sweden and the impact of different treatment strategies

Objective. Recently, new highly effective direct-acting antivirals (DAAs) against hepatitis C virus (HCV) were introduced. Whether these will alleviate the anticipated increase of liver disease burden in Sweden is unknown, partly because high costs may restrict the use. The objectives were to model the HCV epidemic in Sweden, the burden of disease, and the potential impact of different treatment strategies. Material and methods. HCV disease progression was modeled to 2030. Scenarios were simulated using new DAAs with sustained annual treatment rate (n = 1130), reduced treatment rate (n = 380) to maintain budget, and increased treatment rates (n = 1430 or 2260) to reduce HCV infections. Results. With today’s triple therapies, the estimated number of serious liver complications and death are expected to peak in 2021. Using new DAAs among F0–F4 patients, an unchanged annual treatment rate can reduce the number of HCV infections by 10% by 2030; however, hepatocellular carcinoma (HCC) and mortality will remain unchanged. By reducing to 380 treatments annually and focusing on patients with advanced fibrosis (F3–F4), serious complications will remain constant but the total number of HCV infections will increase. By doubling the number of DAA treatments, HCC-incidence and liver-related deaths would decrease by 65–70% by 2030. Conclusion. Mortality and HCC can be reduced with new DAAs and sustained treatment uptake when restricted to F2–F4 patients, or with increased uptake in F0–F4 patients. Treatment restrictions to limit cost may reduce the positive effects and increase the burden of HCV infection. These results may be important for the future strategies of HCV management.

Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: Meta-analysis of 5 trials

HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials. Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring. Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with <3 log10 decline and detectable HCV-RNA at TW8 achieved SVR. Anemia and diarrhea occurred more frequently in cirrhotic than non-cirrhotic patients. Serious AEs, discontinuations due to an AE, interventions to manage anemia, infections, and thrombocytopenia occurred more frequently in cirrhotics with BOC/P/R than P/R. Potential hepatic decompensation and/or sepsis were identified in 2 P/R and 3 BOC/P/R recipients. BOC/P/R appears to have a generally favorable benefit-risk profile in compensated cirrhotic patients. SVR rates were particularly high in cirrhotic patients with undetectable HCV-RNA at TW8.

Should we await IFN-free regimens to treat HCV genotype 1 treatment-naive patients? A cost-effectiveness analysis (ANRS 95141)

In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015). A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3-4/F0-2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0-0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1-10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12weeks of IFN-based new DAAs and two times higher for IFN-free regimens. Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0-1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective. Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.

Effectiveness and Cost-effectiveness of Immediate Versus Delayed Treatment of Hepatitis C Virus–Infected Patients in a Country With Limited Resources: The Case of Egypt

Because of logistical and economic issues, in Egypt, as in other resource-limited settings, decision makers should determine for which patients hepatitis C virus (HCV) treatment should be prioritized. We assessed the effectiveness and cost-effectiveness of different treatment initiation strategies. Using a Markov model, we simulated HCV disease in chronically infected patients in Egypt, to compare lifetime costs, quality-adjusted life expectancy (QALE), and the incremental cost-effectiveness ratio (ICER) of different treatment initiation strategies. Immediate treatment of patients at stages F1/F2/F3 was less expensive and more effective than delaying treatment until more severe stages or not providing treatment (in patients diagnosed at F1: QALE = 18.32 years if treatment at F1 vs 18.22 if treatment at F2). Treatment of F4 patients was more effective than no treatment at all (QALE = 10.33 years vs 8.77 years) and was cost-effective (ICER = $1915/quality-adjusted life-year [QALY]). When considering that affordable triple therapies, including new direct-acting antivirals, will be available starting in 2016, delaying treatment until stage F2, then treating all patients regardless of their disease stage after 2016, was found to be cost-effective (ICER = $33/QALY). In Egypt, immediate treatment of patients with fibrosis stage F1-F3 who present to care is less expensive and more effective than delaying treatment. However, immediate treatment at stage F1 is only slightly more effective than waiting for disease to progress to stage F2 before starting treatment and is sensitive to the forthcoming availability of new treatments. Treating patients at stage F4 is highly effective and cost-effective. In Egypt, decision makers should prioritize treatment for F4 patients and delay treatment for F1 patients who present to care.

Peginterferon plus ribavirin and sustained virological response rate in HCV-related advanced fibrosis: a real life study

BackgroundTolerance and response to antiviral HCV treatment is poor in advanced fibrosis. The aim of this study was to assess SVR rate and its predictive factors in HCV advanced fibrosis patients treated in real life with full dose PEG-IFN plus RBV and to evaluate the adverse events related to treatment. MethodsA multicentric, retrospective study was conducted at six university hospitals. METAVIR F3 and F4 HCV monoinfected patients who were treated with PEG-IFN and RBV had their data analyzed. A stepwise logistic regression analysis was performed to identify the variables independently related to SVR. Adverse events were recorded during treatment. Results308 patients were included, 75% genotype 1 and 23% genotype 3. METAVIR F3 was present in 39% and F4 in 61% of patients. The median Child Pugh score for F4 patients was 5 (5–9). The global SVR rate was 34%, 11% were relapsers and 55% were nonresponders. SVR rates were similar between patients treated with PEG-IFN alfa 2a or alfa 2b (p=0.24). SVR rates according to Child–Pugh score were 26% (Child A) and 18% (Child B). The independent factors related to SVR in F4 patients were genotype 3, RVR and fewer Child Pugh score points. Treatment interruption occurred in 31% patients and death occurred in 1.9%, all with liver cirrhosis. ConclusionTreatment of HCV in patients with advanced fibrosis should not be postponed. However, a very careful evaluation of cirrhotic patients must be performed before treatment is indicated and careful monitoring is required during treatment.

The diagnostic accuracy of Fibroscan® for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response

Transient elastography (TE) is a validated non-invasive tool to evaluate hepatic fibrosis in patients with hepatitis C virus (HCV) infection. Whether TE may sense changes of liver fibrosis following therapeutic HCV eradication has never been evaluated. 37 HCV cirrhotics with paired pre- and post-sustained virological response (SVR) liver biopsies (LB) underwent TE at the time of post-SVR LB. Liver fibrosis was staged with the METAVIR scoring system and the area of fibrosis (%) was assessed morphometrically. Thirty-three patients had valid TE measurements after 61 (48-104) months from an SVR, and 20 (61%) of them had cirrhosis regression. On post-SVR LB, the median area of fibrosis was 2.3%, being significantly reduced from baseline (p<0.0001). Median TE value was 9.8 kPa being lower in regressed vs. not regressed patients (9.1 kPa vs. 12.9 kPa, p=0.01). TE was <12 kPa in 5 (38%) F4 patients and in 19 (95%) ≤F3 patients (p=0.0007). The diagnostic accuracy of TE for diagnosing F4 after treatment was 61% sensitivity, 95% specificity, 12.3 LR+, 0.4 LR-, and AUROC 0.77. A significant correlation was found between TE and both fibrosis stage (r=0.56; p=0.001) and morphometry (r=0.56, p=0.001) as well as between fibrosis stage and area of fibrosis (r=0.72, p=0001). Following therapeutic eradication of HCV, the predictive power of the viremic cut-off of 12 kPa was low as a consequence of liver remodelling and fibrosis reabsorption. LB still remains the only reliable approach to stage liver fibrosis following an SVR.

Ultrasonographic scoring system score versus liver stiffness measurement in prediction of cirrhosis

Background/AimsWe compared the cirrhosis-prediction accuracy of an ultrasonographic scoring system (USSS) combining six representative sonographic indices with that of liver stiffness measurement (LSM) by transient elastography, and prospectively investigated the correlation between the USSS score and LSM in predicting cirrhosis.MethodsTwo hundred and thirty patients with chronic liver diseases (187 men, 43 women; age, 50.4±9.5 y, mean±SD) were enrolled in this prospective study. The USSS produces a combined score for nodularity of the liver surface and edge, parenchyma echogenicity, presence of right-lobe atrophy, spleen size, splenic vein diameter, and abnormality of the hepatic vein waveform. The correlations of the USSS score and LSM with that of a pathological liver biopsy (METAVIR scoring system: F0-F4) were evaluated.ResultsThe mean USSS score and LSM were 7.2 and 38.0 kPa, respectively, in patients with histologically overt cirrhosis (F4, P=0.017) and 4.3 and 22.1 kPa in patients with fibrotic change without overt cirrhosis (F0-F3) (P=0.025). The areas under the receiver operating characteristic (ROC) curves of the USSS score and LSM for F4 patients were 0.849 and 0.729, respectively. On the basis of ROC curves, criteria of USSS ≥6: LSM ≥17.4 had a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 89.2%:77.6%, 69.4%:61.4%, 86.5%:83.7%, 74.6%:51.9% and 0.83:0.73, respectively, in predicting F4.ConclusionsThe results indicate that this USSS has comparable efficacy to LSM in the diagnosis of cirrhosis.

Efficacy and safety of boceprevir plus peginterferon–ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis

We assessed the safety and efficacy of boceprevir (BOC) plus peginterferon-ribavirin (PR) in patients with HCV-G1 infection and advanced fibrosis/cirrhosis (Metavir F3/F4). In two randomized controlled studies of previously untreated and previous treatment failures, patients received a 4-week lead-in of PR followed by PR plus placebo for 44 weeks (PR48); PR plus BOC using response guided therapy (BOC/RGT); or PR plus BOC for 44 weeks (BOC/PR48). The trials enrolled 178 patients with F3/4. HCV RNA levels at week 4 and 8 were highly predictive of response. No patient with F3/4 in the PR48 arm with a <1 log(10) decline in HCV RNA at week 4 achieved SVR, whereas those randomized to BOC/RGT or BOC/PR48 had SVR rates of 11-33% (F3) and 10-14% (F4). In these latter groups, patients with high baseline viral load (>2 × 10(6)IU/ml) had an overall SVR rate of 6% (2/33). For patients with a ≥1 log(10) decline at week 4, SVR rates in the BOC/PR48 arm of SPRINT-2 and RESPOND-2, respectively, were 77% and 87% vs. 18% and 50% for PR48; SVR rates in early responders (undetectable HCV RNA at week 8) were 90-93% in the BOC/PR48 arm. Neutropenia and thrombocytopenia were more common in cirrhotics than non-cirrhotics. BOC improves SVR rates in patients with F3/4, and longer treatment duration provides the most benefit. With triple therapy, SVR rates are modest in F4 patients with a <1 log(10) decline at week 4, thus the 4-week PR lead-in aids in the assessment of early futility.

Potential proteomic biomarkers in assessing liver fibrosis using SELDI-TOF MS

The accurate assessment of the severity of liver fibrosis is of paramount importance in determining treatment strategies, response to treatment and prognosis in patients with chronic liver disease. The aim of this study was to investigate potential proteomic biomarkers for assessing stages of hepatic fibrosis. Serum samples of 83 patients with chronic liver disease (using METAVIR index, 17 F0, 30 F1, 6 F2, 9 F3, and 21 F4 patients) and 29 healthy controls were analyzed using surface-enhanced laser desorption/ionization time-of- flight mass spectrometry on IMAC30 ProteinChip arrays. Discriminatory peaks between groups were identified using Mann-Whitney U non-parametric test. Comparison of mild (F0, F1) and severe fibrosis (F2, F3, F4) was performed using tree classification (cross-validation) with the Biomarker Patterns Software, version 5.0 (Ciphergen Biosystems, US). No statistically significant discriminatory peak was evident between F0, F1 and F2 fibrosis. More than 30 peaks were found to be discriminatory between patients with cirrhosis (F4) and all other stages of liver fibrosis, including F2 and F3. Six surface-enhanced laser desorption/ionization proteomic features were found to be discriminative for mild (F0, F1) vs. advanced (F2, F3, F4) fibrosis (AUROC ≥0.8, p<0.05, Mann-Whitney test). The decision tree (m/z 4280, 10453 and 6376) yielded a sensitivity of 83.3% (30/36), a specificity of 85.1% (40/47), a positive predictive value of 81.1%, and a negative predictive value of 86.9%, with an AUROC of 0.94. The results of this study revealed discriminatory peaks between the protein profiles of patients with cirrhosis and other stages of liver fibrosis. Potential proteomic biomarkers can be notably determined for discriminating mild and advanced fibrosis using surface-enhanced laser desorption/ionization time-of- flight mass spectrometry.

PIN98 Evaluating Optimal Treatment Outcomes of Antiviral Therapy in Hepatitis C for Prior Null Responders in the Era of First Generation Protease Inhibitors

New protease inhibitors (PIs) significantly improve sustained virological responses (SVRs) in patients with genotype 1 chronic hepatitis C. However, treatment (Tx) in prior null-responders with advanced fibrosis often results in failure to achieve SVR and development of resistant mutations. Emerging quadruple Tx adding two direct antiviral agents may achieve SVR in nearly all of these patients. This study aimed to compare two strategies: 1) treating prior null-responders with fibrosis stage 3 (F3) or stage 4 (F4) with telaprevir + peginterferon + ribavirin (“T+P+R strategy”) versus 2) withholding Tx until more effective antiviral agents become available (“Wait strategy”). The MONARCH Hepatitis C cost-effectiveness model was used to project outcomes in cohorts of 55-year-old prior null-responders using published dynamic transition rates for disease progression. “T+P+R strategy” achieves SVR in 42% of F3 and in 14% of F4 patients. In the Wait strategy, patients would wait for 5 years and then initiate quadruple Tx yielding 90% SVR. Quadruple Tx would be used as rescue in patients failing “T+P+R”, 70% of whom would harbor virus resistant to PIs. Patient outcome in terms of SVR and quality-adjusted-life years (QALYs) were assessed 10 years thereafter. Benefits were discounted at 3.5%. Projected SVR rates were higher with the “Wait strategy” (76% and 65% for F3 and F4 respectively) than “T+P+R strategy” (50% and 30% for F3 and F4 respectively). Per-patient expected QALYs were higher for “Wait strategy” than “T+P+R strategy”; 8.59 versus 8.47 QALYs in F3 patients and 7.5 versus 6.7 QALYs in F4 patients. The "Wait strategy" was associated with one-third fewer re-treatments. Waiting for future quadruple antiviral therapy maximized the predicted health benefit both in terms of response (SVR) and QALYs; furthermore, the reduction in re-treatments associated with the "Wait strategy" is noteworthy given the likely high cost of triple therapy.