Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation

BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Adjusted Linear and Logistic Regression for Main Outcome Effects by Late Initial Feedings in a Restricted Cohort of Non-Growth Restricted, Extremely Low Birth Weight (n = 45).

<p>Adjusted Linear and Logistic Regression for Main Outcome Effects by Late Initial Feedings in a Restricted Cohort of Non-Growth Restricted, Extremely Low Birth Weight (n = 45).</p

Maternal and Infant Characteristics of Infants in the Early Feeding Group versus the Late Feeding Group.

<p>Early = initial enteral feeding at the third postnatal day or less</p><p>Late = initial enteral feeding after the third postnatal day</p><p>* Early vs Late p<0.05;</p><p>** Early vs Late p<0.0001.</p><p>Maternal and Infant Characteristics of Infants in the Early Feeding Group versus the Late Feeding Group.</p

Univariate Analysis of Serum Cytokine Expression (in pg/mL) in Association with Early vs. Late Group.

<p>* = Early vs Late p<0.05.</p><p>Univariate Analysis of Serum Cytokine Expression (in pg/mL) in Association with Early vs. Late Group.</p

Nutritional Milestones of Early versus Late Groups.

<p>* Early vs. Late p<0.05</p><p>** Early vs. Late p<0.0001.</p><p>Nutritional Milestones of Early versus Late Groups.</p

Adjusted Logistic Regression for the Odds of CLD and ROP with Late Initiation of Enteral Feedings.

<p>Adjusted Logistic Regression for the Odds of CLD and ROP with Late Initiation of Enteral Feedings.</p

Adjusted Linear Regression Coefficients of Fecal IL-8 Levels and IL-10:IL-8 Ratio with Late Initiation of Feedings and Associated Predictor Variables.

<p>Adjusted Linear Regression Coefficients of Fecal IL-8 Levels and IL-10:IL-8 Ratio with Late Initiation of Feedings and Associated Predictor Variables.</p

Univariate Analysis of Fecal Cytokine Expression in Association with Early vs. Late Groups.

<p>* = Early vs Late p<0.05.</p><p>Univariate Analysis of Fecal Cytokine Expression in Association with Early vs. Late Groups.</p

Univariate Analysis of Neonatal Morbidities by Group.

<p>* Early vs. Late p<0.05;</p><p>** Early vs. Late p<0.0001</p><p>Necrotizing Enterocolitis (NEC); Retinopathy of Prematurity (ROP); Chronic Lung Disease (CLD); Periventricular Leukomalacia (PVL); Intraventricular Hemorrhage (IVH); Cormorbidities = The presence of 2 or more neonatal outcomes.</p><p>Univariate Analysis of Neonatal Morbidities by Group.</p