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The Treatment Cascade for Chronic Hepatitis C Virus Infection in the United States: A Systematic Review and Meta-Analysis

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      Identifying gaps in care for people with chronic hepatitis C virus (HCV) infection is important to clinicians, public health officials, and federal agencies. The objective of this study was to systematically review the literature to provide estimates of the proportion of chronic HCV-infected persons in the United States (U.S.) completing each step along a proposed HCV treatment cascade: (1) infected with chronic HCV; (2) diagnosed and aware of their infection; (3) with access to outpatient care; (4) HCV RNA confirmed; (5) liver fibrosis staged by biopsy; (6) prescribed HCV treatment; and (7) achieved sustained virologic response (SVR).


      We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews for articles published between January 2003 and July 2013. Two reviewers independently identified articles addressing each step in the cascade. Studies were excluded if they focused on specific populations, did not present original data, involved only a single site, were conducted outside of the U.S., or only included data collected prior to 2000.


      9,581 articles were identified, 117 were retrieved for full text review, and 10 were included. Overall, 3.5 million people were estimated to have chronic HCV in the U.S. Fifty percent (95% CI 43–57%) were diagnosed and aware of their infection, 43% (CI 40–47%) had access to outpatient care, 27% (CI 27–28%) had HCV RNA confirmed, 17% (CI 16–17%) underwent liver fibrosis staging, 16% (CI 15–16%) were prescribed treatment, and 9% (CI 9–10%) achieved SVR.


      Continued efforts are needed to improve HCV care in the U.S. The proposed HCV treatment cascade provides a framework for evaluating the delivery of HCV care over time and within subgroups, and will be useful in monitoring the impact of new screening efforts and advances in antiviral therapy.

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      Most cited references 42

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      Quantifying heterogeneity in a meta-analysis.

      The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity. Copyright 2002 John Wiley & Sons, Ltd.
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        Management of hepatocellular carcinoma: An update

        Since the publication of the American Association for the Study of Liver Diseases (AASLD) practice guidelines on the management of hepatocellular carcinoma (HCC) in 2005, new information has emerged that requires that the guidelines be updated. The full version of the new guidelines is available on the AASLD Web site at Here, we briefly describe only new or changed recommendations. Surveillance and Diagnosis In the previous guideline, groups were specified for which surveillance was likely to be cost-effective because the hepatocellular carcinoma (HCC) incidence was high enough. New data on defining HCC risk have emerged for hepatitis B virus,1,2 hepatitis C virus,3 and autoimmune hepatitis.4 Surveillance is deemed cost-effective if the expected HCC risk exceeds 1.5% per year in patients with hepatitis C and 0.2% per year in patients with hepatitis B. Analysis of recent studies show that alpha-fetoprotein determination lacks adequate sensitivity and specificity for effective surveillance (and for diagnosis).5,6 Thus, surveillance has to be based on ultrasound examination. The recommended screening interval is 6 months. Diagnosis of HCC should be based on imaging techniques and/or biopsy.The 2005 diagnostic algorithm has been validated and the diagnostic accuracy of a single dynamic technique showing intense arterial uptake followed by “washout” of contrast in the venous-delayed phases has been demonstrated.7-9 Contrast-enhanced US may offer false positive HCC diagnosis in patients with cholangiocarcinoma and thus, has been dropped from the diagnostic techniques. The diagnostic algorithm is shown in Fig. 1. The application of dynamic imaging criteria should be applied only to patients with cirrhosis of any etiology and to patients with chronic hepatitis B who may not have fully developed cirrhosis or have regressed cirrhosis. Interpretation of biopsies and distinction between high-grade dysplatic nodules and HCC is challenging. Expert pathology diagnosis is reinforced by staining for glypican 3, heat shock protein 70, and glutamine synthetase, because positivity for two of these three stains confirms HCC.10 Fig. 1 Diagnostic algorithm for suspected HCC. CT, computed tomography; MDCT, multidetector CT; MRI, magnetic resonance imaging; US, ultrasound. Staging and Treatment of HCC The BCLC staging system (Fig. 2)11 has come to be widely accepted in clinical practice and is also being used for many clinical trials of new drugs to treat HCC. Therefore, it has become the de facto staging system that is used. Fig. 2 The BCLC staging system for HCC. M, metastasis classification; N, node classification; PS, performance status; RFA, radiofrequency ablation; TACE, transarterial chemoembolization. The recommendations for liver transplantation have not changed. No new data have emerged that can be used to define a new limit for expanding the patient selection criteria. The usefulness of portal pressure measurement to predict the outcome of patients and define optimal candidates for resection has been validated in Japan.12 Thus, resection should remain the first option for patients who have the optimal profile, as defined by the BCLC staging system. Although resection can be performed in some of these patients with advanced liver disease, the mortality is higher and they might be better served by liver transplantation or ablation. A cohort study of radiofrequency ablation demonstrated that complete ablation of lesions smaller than 2 cm is possible in more than 90% of cases, with a local recurrence rate of less than 1%.13 These data should be confirmed by other groups before positioning ablation as the first-line approach for very early HCC. The recommendations regarding patient selection and method of administration of chemoembolization are unchanged. Radioembolization, i.e., the intra-arterial injection of yttrium-90 bound to glass beads or to resin, has been shown to induce tumor necrosis, but there are no data comparing its efficacy to transarterial chemoembolization or to sorafenib treatment for those with portal vein invasion. However, for patients who have either failed transarterial chemoembolization or who present with more advanced HCC, new data indicates the efficacy of sorafenib (a multikinase inhibitor with activity against Raf-1, B-Raf, vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, c-Kit receptors, among other kinases) in prolonging life.14,15 Sorafenib induces a clinically relevant improvement in time to progression and in survival The magnitude of the improvement in survival compares with other established molecular targeted therapies for other advanced cancers, and the associated toxicity is easily managed without treatment-related mortality. The most frequent adverse events were diarrhea (sorafenib versus placebo: 11% versus 2%) and hand–foot skin reaction (sorafenib versus placebo: 8% versus <1%), fatigue, and weight loss. Sorafenib is now considered first-line treatment in patients with HCC who can no longer be treated with potentially more effective therapies. In summary, in the past decade HCC has gone from being an almost universal death sentence to a cancer that can be prevented, detected at an early stage, and effectively treated. Physicians caring for patients at risk need to provide high-quality screening, proper management of screen-detected lesions, and provision of therapy that is most appropriate for the stage of disease.
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          Diagnosis, management, and treatment of hepatitis C: an update.

           L. Thomas,  ,  Marc G Ghany (2009)

            Author and article information

            [1 ]Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
            [2 ]Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
            [3 ]Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
            [4 ]Department of Medicine, New York University School of Medicine, New York, New York, United States of America
            [5 ]Center for Evidenced-Based Practice, University of Pennsylvania Health System, Philadelphia, Pennsylvania, United States of America
            Mayo Clinic, United States of America
            Author notes

            Competing Interests: BRY receives investigator-initiated research support (to the University of Pennsylvania) from Gilead Sciences; AJS has no such interests; CAU has no such interests; VLR receives investigator-initiated research support (to the University of Pennsylvania) from AstraZeneca, Bristol Myers-Squibb, Merck, and Gilead Sciences. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

            Conceived and designed the experiments: BRY AJS CAU VLR. Performed the experiments: BRY AJS CAU VLR. Analyzed the data: BRY AJS CAU VLR. Wrote the paper: BRY AJS CAU VLR.

            Role: Editor
            PLoS One
            PLoS ONE
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            2 July 2014
            : 9
            : 7
            24988388 4079454 PONE-D-14-06670 10.1371/journal.pone.0101554

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Pages: 7
            This work was supported by the National Institutes of Health [K23 MH097647 to BRY and K01 AI070001 to VLR]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Research Article
            Medicine and health sciences
            Gastroenterology and hepatology
            Liver diseases
            Infectious hepatitis
            Hepatitis C
            Health Care
            Health Care Quality
            Infectious Diseases
            Viral Diseases



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