Background

Biopsy for Chronic Liver Disease

The diagnosis of non-neoplastic liver disease is often made from needle biopsy samples. In addition to establishing a disease etiology, liver biopsy can determine the degree of inflammation present and can stage the degree of fibrosis. The degree of inflammation and fibrosis may be assessed by different scoring schemes. Most of these scoring schemes grade inflammation from 0 (no or minimal inflammation) to 4 (severe) and fibrosis from 0 (no fibrosis) to 4 (cirrhosis). There are several limitations to liver biopsy, including its invasive nature, small tissue sample size, and subjective grading system. Regarding small tissue sample size, liver fibrosis can be patchy and thus missed on a biopsy sample, which includes only 0.002% of the liver tissue. A noninvasive alternative to liver biopsy would be particularly helpful, both to initially assess patients and then to monitoring response to therapy. The implications of using liver biopsy as a reference standard are discussed in the Rationale.

Hepatitis C Virus

Infection with HCV can lead to permanent liver damage. Prior to noninvasive testing, liver biopsy was typically recommended before the initiation of antiviral therapy. Repeat biopsies may be performed to monitor fibrosis progression. Liver biopsies are analyzed according to a histologic scoring system; the most commonly used one for HCV is the Metavir scoring system, which scores the presence and degree of inflammatory activity and fibrosis. The fibrosis is graded from F0 to F4, with a Metavir score of F0 signifying no fibrosis and F4 signifying cirrhosis (which is defined as the presence throughout the liver of fibrous septa that subdivide the liver parenchyma into nodules and represents the final and irreversible form of the disease). The stage of fibrosis is the most important single predictor of morbidity and mortality in patients with hepatitis C. Biopsies for HCV are also evaluated according to the degree of inflammation present, referred to as the grade or activity level. For example, the Metavir system includes scores for necroinflammatory activity ranging from A0 to A3 (A0 = no activity, A1 = minimal activity, A2 = moderate activity, A3 = severe activity).

Hepatitis B Virus

Most people who become infected with the HBV recover fully, but a small portion develops chronic HBV, which can lead to permanent liver damage. As with HCV, identification of liver fibrosis is needed to determine timing and management of treatment, and liver biopsy is the criterion standard for staging fibrosis. The grading of fibrosis in HBV also uses the Metavir system.

Alcoholic Liver Disease

ALD is the leading cause of liver disease in most Western countries. Histologic features of ALD usually include steatosis, alcoholic steatohepatitis, hepatocyte necrosis, Mallory bodies (tangled proteins seen in degenerating hepatocytes), a large polymorphonuclear inflammatory infiltrate, and, with continued alcohol abuse, fibrosis, and possibly cirrhosis. The grading of fibrosis is similar to the scoring system used in HCV. The commonly used Laënnec scoring system uses grades 0 to 4, with 4 being cirrhosis.

Nonalcoholic Fatty Liver Disease

NAFLD is defined as a condition that pathologically resembles ALD but occurs in patients who are not heavy users of alcohol. Moreover, NAFLD may be associated with a variety of conditions, including obesity, diabetes, and dyslipidemia. The characteristic feature of NAFLD is steatosis. At the benign end of the disease spectrum, there is usually no appreciable inflammation, hepatocyte death, or fibrosis. In contrast, nonalcoholic steatohepatitis (NASH), which shows overlapping histologic features with ALD, is an intermediate form of liver damage, and liver biopsy may show steatosis, Mallory bodies, focal inflammation, and degenerating hepatocytes. NASH can progress to fibrosis and cirrhosis. A variety of histologic scoring systems have been used to evaluate NAFLD. The NAFLD Activity Score system for NASH includes scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2). Cases with scores of 5 or greater are considered NASH, while cases with scores of 3 and 4 are considered borderline (probable or possible) NASH. The grading of fibrosis is similar to the scoring system used in hepatitis C. The commonly used Laënnec scoring system uses grades 0 to 4, with 4 being cirrhosis.

Noninvasive Alternatives to Liver Biopsy

Multianalyte Assays

A variety of noninvasive laboratory tests are being evaluated as alternatives to liver biopsy. Biochemical tests can be broadly categorized into indirect and direct markers of liver fibrosis. Indirect markers include liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), the ALT/AST ratio (also referred to as the AAR), platelet count, and prothrombin index. There has been a growing understanding of the underlying pathophysiology of fibrosis, leading to a direct measurement of the factors involved. For example, the central event in the pathophysiology of fibrosis is the activation of the hepatic stellate cell. Normally, stellate cells are quiescent but are activated in the setting of liver injury, producing a variety of extracellular matrix (ECM) proteins. In normal livers, the rate of ECM production equals its degradation, but with fibrosis, production exceeds degradation. Metalloproteinases are involved in intracellular degradation of ECM, and a profibrogenic state exists when there is either a down-regulation of metalloproteinases or an increase in tissue inhibitors of metalloproteinases. Both metalloproteinases and tissue inhibitors of metalloproteinases can be measured in the serum, which directly reflects the fibrotic activity. Other direct measures of ECM deposition include hyaluronic acid or α₂-macroglobulin.

While many studies have been done on these individual markers, or on groups of markers in different populations of patients with liver disease, there has been interest in analyzing multiple markers using mathematical algorithms to generate a score that categorizes patients according to the biopsy score. It is proposed that these algorithms can be used as alternatives to liver biopsy in patients with liver disease. The following proprietary, algorithm-based tests are commercially available in the U. S.

FibroSURE

HCV FibroSURE

The HCV FibroSURE uses a combination of six serum biochemical indirect markers of liver function plus age and sex in a patented algorithm to generate a measure of fibrosis and necroinflammatory activity in the liver that corresponds to the Metavir scoring system for stage (i.e., fibrosis) and grade (i.e., necroinflammatory activity). The measures are combined using a linear regression equation to produce a score between 0 and 1, with higher values corresponding to more severe disease. The biochemical markers include the readily available measurements of α₂-macroglobulin, haptoglobin, bilirubin, γ-glutamyl transpeptidase, ALT, and apolipoprotein AI. Developed in France, the test has been clinically available in Europe under the name FibroTest since 2003; it is exclusively offered by LabCorp in the U. S. as HCV FibroSURE.

ASH FibroSURE

ASH FibroSURE (ASH Test) uses a combination of ten serum biochemical markers of liver function together with age, sex, height, and weight in a proprietary algorithm; the test is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and ASH. The biochemical markers include α₂-macroglobulin, haptoglobin, apolipoprotein AI, bilirubin, γ-glutamyl transpeptidase, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name AshTest™ (BioPredictive); the test is exclusively offered by LabCorp in the U. S. as ASH FibroSURE.

NASH FibroSURE

NASH FibroSURE (NASH Test) uses a proprietary algorithm of the same ten biochemical markers of liver function in combination with age, sex, height, and weight and is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and NASH. The biochemical markers include α₂-macroglobulin, haptoglobin, apolipoprotein AI, bilirubin, γ-glutamyl transpeptidase, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name NashTest™ (BioPredictive); the test is exclusively offered by LabCorp in the U. S. as NASH FibroSURE.

FIBROSpect II

FIBROSpect II uses a combination of three markers that directly measure fibrogenesis of the liver, analyzed with a patented algorithm. The markers include hyaluronic acid, tissue inhibitor of metalloproteinase 1, and α₂-macroglobulin. FIBROSpect II is offered exclusively by Prometheus Laboratories. The measures are combined using a logistic regression algorithm to generate a FIBROSpect II index score, ranging from 1 to 100 (or sometimes reported between 0 and 1), with higher scores indicating more severe disease.

Noninvasive Imaging Technologies

Noninvasive imaging technologies to detect liver fibrosis or cirrhosis among patients with chronic liver disease are being evaluated as alternatives to liver biopsy. The noninvasive imaging technologies include transient elastography (e.g., FibroScan), magnetic resonance elastography, acoustic radiation force impulse (ARFI) imaging (e.g., Acuson S2000), and real-time tissue elastography (e.g., HI VISION Preirus). Noninvasive imaging tests have been used in combination with multianalyte serum tests such as FibroTest or FibroSURE with FibroScan.

Transient Elastography

Transient elastography (FibroScan) uses a mechanical vibrator to produce mild amplitude and low-frequency (50 Hz) waves, inducing an elastic shear wave that propagates throughout the liver. Ultrasound tracks the wave, measuring its speed in kilopascals, which correlates with liver stiffness. Increases in liver fibrosis also increase liver stiffness and resistance of liver blood flow. Transient elastography does not perform as well in patients with ascites, higher body mass index, or narrow intercostal margins. Although FibroScan may be used to measure fibrosis (unlike liver biopsy), it does not provide information on necroinflammatory activity and steatosis, nor is it accurate during acute hepatitis or hepatitis exacerbations.

ARFI Imaging

ARFI imaging uses an ultrasound probe to produce an acoustic “push” pulse, which generates shear waves that propagate in tissue to assess liver stiffness. ARFI elastography evaluates the wave propagation speed (measured in meters per second) to assess liver stiffness. The faster the shear wave speed, the harder the object. ARFI technologies include Virtual Touch Quantification and Siemens Acuson S2000 system. ARFI elastography can be performed at the same time as a liver sonographic evaluation, even in patients with a significant amount of ascites.

Magnetic Resonance Elastography

Magnetic resonance elastography uses a driver to generate 60-Hz mechanical waves on the patient’s chest wall. The magnetic resonance equipment creates elastograms by processing the acquired images of propagating shear waves in the liver using an inversion algorithm. These elastograms represent the shear stiffness as a pixel value in kilopascals. Magnetic resonance elastography has several advantages over ultrasound elastography, including: (1) the ability to analyze larger liver volumes; (2) the ability to analyze liver volumes of obese patients or patients with ascites; and (3) the ability to precisely analyze viscoelasticity using a 3-dimensional displacement vector.

Real-Time Tissue Elastography

Real-time tissue elastography is a type of strain elastography that uses a combined autocorrelation method to measure tissue strain caused by manual compression or a person’s heartbeat. The relative tissue strain is displayed on conventional color B mode ultrasound images in real-time. Hitachi manufactures real-time tissue elastography devices, including the HI VISION Preirus. The challenge is to identify a region of interest while avoiding areas likely to introduce artifacts, such as large blood vessels, the area near the ribs, and the surface of the liver. Areas of low strain increase as fibrosis progresses and strain distribution becomes more complex. Various subjective and quantitative methods have been developed to evaluate the results. Real-time tissue elastography can be performed in patients with ascites or inflammation. This technology does not perform as well in severely obese individuals.

Regulatory Status

In 2008 Acuson S2000™ Virtual Touch (Siemens AG), which provides ARFI imaging, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process (K072786)(K123622).

In 2009, AIXPLORER® Ultrasound System (SuperSonic Imagine), which provides shear wave elastography, was cleared for marketing by the FDA through the 510(k) process (K091970).

In 2010, Hitachi HI VISION™ Preirus™ Diagnostic Ultrasound Scantier (Hitachi Medical Systems America), which provides real-time tissue elastography, was cleared for marketing by the FDA through the 510(k) process (K093466).

In 2013, FibroScan® (EchoSens), which uses transient elastography, was cleared for marketing by the FDA through the 510(k) process (K123806).

In February 2017, ElastQ Imaging shear wave elastography (Royal Phillips) was cleared for marketing by the FDA through the 510(k) process (K163120).

FDA product code: IYO.

In November 2018, the FDA granted a Breakthrough Device designation for the ADVIA Centaur Enhanced Liver Fibrosis (ELF^TM) Test (Siemens Healthcare).^1, At this time, the Enhanced Liver Fibrosis Test is currently only available for use outside of the U. S.

Related Policies

• None

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Noninvasive Testing for Chronic Liver Disease

As noted in the Background, liver biopsy is an imperfect reference standard. There is a high rate of sampling error in the biopsy, which can lead to underdiagnosis of liver disease.^2,3, These errors will bias estimates of performance characteristics of the noninvasive tests to which it is compared, and therefore such errors must be considered in apprising the body of evidence. Mehta et al (2009) estimated that even under the best scenario where sensitivity and specificity of liver biopsy are 90%, and the prevalence of significant disease (increased liver fibrosis, scored as Metavir ≥ F2) is 40%-a perfect alternative marker would have calculated area under the receiver operating characteristic (AUROC) curve of 0.90.^4, Therefore, the effectiveness of alternative technologies may be underestimated. In fact, when the accuracy of biopsy is presumed to be 80%, a comparative technology with an AUROC curve of 0.76 may actually have an AUROC curve of 0.93 to 0.99 for diagnosing true disease.

Due to a large number of primary studies published on this topic, this policy focuses on systematic reviews when available. The validation of multiple noninvasive tests is assessed individually in the following sections. Although options exist for performing systematic reviews with imperfect reference standards,^5, most available reviews did not use any correction for the imperfect reference.

A systematic review by Crossan et al (2015) was performed for the National Institute for Health Research.^6, The first objective of the review was to determine the diagnostic accuracy of different noninvasive liver tests compared with liver biopsy in the diagnosis and monitoring of liver fibrosis and cirrhosis in patients with hepatitis C virus (HCV), hepatitis B virus (HBV), nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Reviewers selected 302 publications and presentations from 1998 to April 2012. Patients with HCV were the most common population included in the studies while patients with ALD were the least common. FibroScan and FibroTest were the most commonly assessed tests across liver diseases. Aminotransferase to platelet ratio index (APRI) was also widely assessed in HBV and HCV but not in NAFLD or ALD. The estimates of diagnostic accuracy for each test by disease (as determined by Crossan et al [2015]) are discussed in further detail in the following sections. Briefly, for diagnosing significant fibrosis (stage ≥ F2) in HCV, the summary sensitivities and specificities were: FibroScan, 79% and 83%; FibroTest, 68% and 72%; APRI (low cutoff), 82% and 57%; acoustic radiation force impulse (ARFI) imaging, 85% and 89%; HepaScore, 73% and 73%, FIBROSpect II, 78% and 71%; and FibroMeter, 79% and 73%, respectively. For diagnosing advanced fibrosis in HBV, the summary sensitivities and specificities were: FibroScan, 71% and 84%; FibroTest, 66% and 80%, respectively. There are no established or validated cutoffs for fibrosis stages across the diseases for most tests. For FibroTest, established cutoffs exist but were used inconsistently across studies. Test failures or reference standard(s) were frequently not captured in analyses. Most populations included in the studies were from tertiary care settings who have themore advanced disease than the general population, which would overestimate the prevalence of the disease and diagnostic accuracy. These issues likely cause overestimates of sensitivities and specificities. The quality of the studies was generally rated as poor, with only 1.6% receiving a high-quality rating.

Houot et al (2016) reported on a systematic review funded by BioPredictive, the manufacturer of FibroTest.^7, Reviewers included 71 studies published between January 2002 to February 2014 with over 12000 participants with HCV and HBV comparing the diagnostic accuracy of FibroTest, FibroScan, APRI, and fibrosis-4 (FIB-4) index. Reviewers included studies that directly compared the tests and calculated median differences in the AUROC using Bayesian methods. There was no evaluation of the methodologic quality of the included studies. The Bayesian difference in AUROC curve for significant fibrosis (stage ≥ F2) between FibroTest and FibroScan was based on 15 studies and estimated to be 0.06 (95% credible interval [CrI], 0.02 to 0.09) favoring FibroTest. The difference in AUROC curve for cirrhosis for FibroTest vs FibroScan was based on 13 studies and estimated to be 0.00 (95% CrI, 0.04 to 0.04). The difference for advanced fibrosis between FibroTest and APRI was based on 21 studies and estimated to be 0.05 (95% CrI, 0.03 to 0.07); for cirrhosis, it was based on 14 studies and estimated to be 0.05 (95% CrI, 0.00 to 0.11), both favoring FibroTest.

Multianalyte Serum Assays: FibroSURE (FibroTest)

Clinical Context and Test Purpose

The purpose of noninvasive testing in individuals with chronic liver disease is to detect liver fibrosis so that patients can avoid the potential adverse events of an invasive liver biopsy and receive appropriate treatment. The degree of liver fibrosis is an important factor in determining the appropriate approach for managing patients with liver disease (e.g., hepatitis, ALD, NAFLD).

The question addressed in this portion of the policy is: Does the use of the FibroSURE multianalyte serum assay for detecting liver fibrosis improve the net health outcome in patients with chronic liver disease?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with chronic liver disease.

Interventions

The test being considered is the FibroSURE serum panel.

Comparators

The following tests and practices are currently being used to diagnose chronic liver disease: liver biopsy, noninvasive radiologic methods, and other multianalyte serum assays.

Outcomes

The general outcomes of interest are test validity, morbid events, and treatment-related morbidity. Follow-up over months to years is of interest to the relevant outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of this test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
• Included a suitable reference standard (describe the reference standard)
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Hepatitis C Virus

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Initial research into the HCV FibroSURE algorithm involved testing an initial panel of 11 serum markers in 339 patients with liver fibrosis who had undergone liver biopsy. From the original group of 11 markers, 5 were selected as the most informative, based on logistic regression, neural connection, and receiver operating characteristic (ROC) curves. Markers included α₂-macroglobulin, haptoglobin, γ-globulin, apolipoprotein AI, γ-glutamyl transpeptidase, and total bilirubin.^8, Using an algorithm-derived scoring system ranging from 0 to 1.0, authors reported that a score of less than 0.10 was associated with a negative predictive value (NPV) of 100% (i.e., the absence of fibrosis, as judged by liver biopsy scores of Metavir F2-F4). A score greater than 0.60 was associated with a 90% positive predictive value (PPV) of fibrosis (i.e., Metavir F2-F4). Authors concluded that liver biopsy might be deferred in patients with a score of less than 0.10.

The next step in the development of this test was further evaluation of the algorithm in a cross-section of patients, including patients with HCV participating in large clinical trials before and after the initiation of antiviral therapy. A study by Poynard et al (2003) focused on patients with HCV participating in a randomized study of pegylated interferon and ribavirin.^9, From the 1530 participants, 352 patients with stored serum samples and liver biopsies at study entry and at 24-week follow-up were selected. The HCV FibroSURE score was calculated and then compared with the Metavir liver biopsy score. At a cutoff of 0.30, the HCV FibroSURE score had 90% sensitivity and 88% PPV for the diagnosis of Metavir F2-F4 fibrosis. The specificity was 36%, and the NPV was 40%.

Poynard et al (2004) also evaluated discordant results in 537 patients who underwent liver biopsy and the HCV FibroSURE and ActiTest on the same day; discordance was attributed to either the limitations in the biopsy or serum markers.^10, In this study, cutoff values were used for individual Metavir scores (i.e., F0-F4) and for combinations of Metavir scores (i.e., F0-F1, F1-F2). The definition of a significant discordance between FibroTest and ActiTest and biopsy scores was at least two stages or grades in the Metavir system. Discordance was observed in 29% of patients. Risk factors for failure of the HCV FibroSURE scoring system were as follows: the presence of hemolysis, inflammation, possible Gilbert syndrome, acute hepatitis, drugs inducing cholestasis, or an increase in transaminases. Discordance was attributable to markers in 2.4% of patients, to the biopsy in 18%, and nonattributed in 8.2% of patients. As noted in two reviews, the bulk of the research on HCV FibroSURE was conducted by researchers with an interest in the commercialization of the algorithm.^11,12,

An Australian study reported by Rossi et al (2003) attempted to independently replicate the results of FibroSURE in 125 patients with hepatitis C.^13, Using the cutoff of less than 0.1 to identify lack of bridging fibrosis (i.e., Metavir stages F0-F1) and greater than 0.6 to identify fibrosis (i.e., Metavir stages F2-F4), the NPV for a score of less than 0.1 was 89%, and the PPV of a score greater than 0.6 was 78%.

Poynard et al (2012) assessed the relative accuracy of FibroTest and FibroScan using a method to estimate performance characteristics when no perfect reference standard exists.^14, The study included 1893 subjects retrospectively extracted from 4 prospective cohorts: 3 cohorts with HCV (n=1289) and a cohort of healthy volunteers (n=604). Four different tests (FibroTest, FibroScan, alanine aminotransferase [ALT], liver biopsy) were performed on all patients with HCV. Latent class models with random effects were used to combine the test results to construct a reference standard. Compared with biopsy as the reference standard, the sensitivity and specificity for the diagnosis of advanced fibrosis were 85% and 66% for FibroTest and 93% and 48% for FibroScan, respectively. However, when compared to the latent class reference standard, the specificity and sensitivity for the diagnosis of advanced fibrosis were 93% and 70% for FibroTest and 96% and 45%, for FibroScan, respectively.

In the Crossan et al (2015) systematic review, FibroTest was the most widely validated commercial serum test.^6, Seventeen studies were included in the pooled estimate of the diagnostic accuracy of FibroTest for significant fibrosis (stage ≥ F2) in HCV. With varying cutoffs for positivity between 0.32 and 0.53, the summary sensitivity in HCV was 68% (95% confidence interval [CI], 58% to 77%) and specificity was 72% (95% CI, 70% to 77%). Eight studies were included for cirrhosis (stage F4) in HCV. The cutoffs for positivity ranged from 0.56 to 0.74 and the summary sensitivity and specificity were 60% (95% CI, 43% to 76%) and 86% (95% CI, 81% to 91%), respectively. Uninterpretable results were rare for tests based on serum markers.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

The primary benefit of the FibroSURE (FibroTest in Europe) for HCV is the ability to avoid liver biopsy in patients without significant fibrosis. Thus, empirical data are needed that demonstrate that the FibroSURE test impacts clinician decision making on whether a biopsy should be performed and that the net effect is to reduce the overall number of biopsies while achieving similar clinical outcomes. There are currently no such published studies to demonstrate the effect on patient outcomes.

The FibroTest has been used as an alternative to biopsy for the purposes of establishing trial eligibility in terms of fibrosis or cirrhosis; and several trials (ION-1,-3; VALENCE; ASTRAL-2, -3, -4) have established the efficacy of HCV treatments.^{15,16,17,18,19,20,} For example, in the ASTRAL-2 and -3 trials, cirrhosis could be defined by a liver biopsy; a FibroScan or a FibroTest score of more than 0.75; or an APRI of more than 2.

These tests also need to be adequately compared with other noninvasive tests of fibrosis to determine their comparative efficacy-in particular, the proprietary, algorithmic tests should demonstrate superiority to other readily available, nonproprietary scoring systems to demonstrate that the tests improve health outcomes.

The FibroSURE test also has a potential effect on patient outcomes as a means to follow response to therapy. In this case, evidence needs to demonstrate that the use of the test for response to therapy impacts decision making and that these changes in management decisions lead to improved outcomes. It is not clear whether the HCV FibroSURE could be used as an interval test in patients receiving therapy to determine whether an additional liver biopsy was necessary.

Alcoholic Liver Disease and Alcoholic Steatohepatitis

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The diagnostic value of FibroSURE (FibroTest in Europe) has also been evaluated for the prediction of liver fibrosis in patients with ALD and NAFLD.^21,22, Thabut et al (2006) reported the development of a panel of biomarkers (ASH FibroSURE [ASH Test]) for the diagnosis of alcoholic steatohepatitis (ASH) in patients with chronic ALD.^23, Biomarkers were initially assessed in a training group of 70 patients, and a panel was constructed using a combination of the 6 biochemical components of the FibroTest-ActiTest plus aspartate aminotransferase (AST). The algorithm was subsequently studied in 2 validation groups (1 prospective study for severe ALD, 1 retrospective study for nonsevere ALD) that included 155 patients and 299 controls. The severity of ASH (none, mild, moderate, severe) was blindly assessed from biopsy samples. In the validation groups, there were 28 (18%) cases of discordance between the diagnosis of ASH predicted by the ASH Test and biopsy; 10 (36%) were considered false-negatives of the ASH Test, and 11 were suspected failures of biopsy. Seven cases were indeterminate by biopsy. The AUROC curves were 0.88 and 0.89 in the validation groups. The median ASH Test value was 0.005 in controls, 0.05 in patients without or with mild ASH, 0.64 in the moderate ASH grade, and 0.84 in severe ASH grade 3. Using a cutoff value of 0.50, the ASH Test had a sensitivity of 80% and specificity of 84%, with PPVs and NPVs of 72% and 89%, respectively.

Several authors have an interest in the commercialization of this test, and no independent studies on the diagnostic accuracy of ASH FibroSURE (ASH Test) were identified. In addition, it is not clear if the algorithm used in this study is the same as that used in the currently commercially available test, which includes ten biochemicals.

FibroTest has been studied in patients with ALD. In the Crossan et al (2015) systematic review, 1 study described the diagnostic accuracy of FibroTest for significant fibrosis (stage ≥ F2) or cirrhosis in ALD.^6, With a high cutoff for positivity (0.7), the sensitivity and specificity for advanced fibrosis were 55% (95% CI, 47% to 63%) and 93% (95% CI, 85% to 97%) and for cirrhosis were 91% (95% CI, 82% to 96%) and 87% (95% CI, 81% to 91%), respectively. With a low cutoff for positivity (0.3), the sensitivity and specificity for advanced fibrosis were 84% (95% CI, 77% to 89%) and 65% (95% CI, 55% to 75%), respectively. The sensitivity and specificity for cirrhosis were 100% (95% CI, 95% to 100%) and 50% (95% CI, 42% to 58%), respectively.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No studies were identified that assessed clinical outcomes following the use of the ASH FibroSURE (ASH Test).

Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Poynard et al (2006) reported the development of a panel of biomarkers (NASH FibroSURE [NASH Test]) for the prediction of nonalcoholic steatohepatitis (NASH) in patients with NAFLD.^24, Biomarkers were initially assessed with a training group of 160 patients, and a panel was constructed using a combination of 13 of 14 parameters of the currently available test. The algorithm was subsequently studied in a validation group of 97 patients and 383 controls. Patients in the validation group were from a prospective multicenter study with hepatic steatosis at biopsy and suspicion of NAFLD. Histologic diagnoses used Kleiner et al’s scoring system, with 3 classes for NASH (NASH, borderline NASH, no NASH). The main endpoint was steatohepatitis, defined as a histologic NASH score of five or greater. The AUROC curve for the validation group was 0.79 for the diagnosis of NASH, 0.69 for the diagnosis of borderline NASH, and 0.83 for the diagnosis of no NASH. Results showed a sensitivity of 33% and specificity of 94% for NASH, with a PPV and NPV of 66% and 81%, respectively. For borderline NASH or NASH, sensitivity was 88%, specificity 50%, PPV 74%, and NPV 72%. Clinically significant discordance (2 class difference) was observed in 8 (8%) patients. None of the 383 controls was considered to have NASH by NASH FibroSURE (NASH Test). Authors proposed that this test would be suitable for mass screening for NAFLD in patients with obesity and diabetes.

An independent study by Lassailly et al (2011) attempted to prospectively validate the NashTest (along with the FibroTest, SteatoTest, and ActiTest) in a cohort of 288 patients treated with bariatric surgery.^23, Included were patients with severe or morbid obesity (body mass index, >35 kg/m²), at least 1 comorbidity for at least 5 years, and resistance to medical treatment. Excluded were patients with current excessive drinking, long-term consumption of hepatotoxic drugs, and positive screening for chronic liver diseases including hepatitis. Histology and biochemical measurements were centralized and blinded to other characteristics. The NashTest provided a 3-category score for no NASH (0.25), possible NASH (0.50), and NASH (0.75). The prevalence of NASH was 6.9%, while the prevalence of NASH or possible NASH was 27%. The concordance rate between the histologic NASH score and the NashTest was 43.1%, with a weak κ reliability test (0.14). In 183 patients categorized as possible NASH by the NashTest, 124 (68%) were classified as no NASH by biopsy. In 15 patients categorized as NASH by the NashTest, 7 (47%) were no NASH and 4 (27%) were possible NASH by biopsy. The NPV of the NashTest for possible NASH or NASH was 47.5%. Authors suggested that the power of this study to validate agreement between the NashTest and biopsy was low, due to the low prevalence of NASH. However, the results showed poor concordance between the NashTest and biopsy, particularly for intermediate values.

In the Crossan et al (2015) systematic review, 4 studies were included in the pooled estimate of the diagnostic accuracy of FibroTest for advanced fibrosis (stage ≥ 3) in NAFLD.^6, The summary sensitivities and specificities were 40% (95% CI, 24% to 58%) and 96% (95% CI, 91% to 98%), respectively. Only 1 study included reported accuracy for cirrhosis, with sensitivity and specificity of 74% (95% CI, 54%, to 87%) and 92% (95% CI, 88% to 95%), respectively.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No studies were identified that assessed clinical outcomes following the use of the NASH FibroSURE (NASH Test).

Hepatitis B Virus

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

While most multianalyte assay studies that have identified fibrosis have been conducted in patients with HCV, studies are also being conducted in patients with chronic HBV.^24,25, In a study, Park et al (2013) compared liver biopsy with the FibroTest results obtained on the same day from 330 patients who had chronic HBV.^26, Discordance was found in 30 (9.1%) patients for whom the FibroTest underestimated fibrosis in 25 patients and overestimated it in 5 patients. Those with Metavir liver fibrosis stage F3 or F4 (15.4%) had a significantly higher discordance rate than those with stages F1 or F2 (3.0%; p<0.001). The only independent factor for discordance on multivariate analysis was a Metavir stage F3 or F4 on liver biopsy (p<0.001).

Salkic et al (2014) conducted a meta-analysis of studies on the diagnostic accuracy of FibroTest in chronic HBV.^27, Included in the meta-analysis were 16 studies (2494 patients) on liver fibrosis diagnosis and 13 studies (1754 patients) on cirrhosis diagnosis. There was strong evidence of heterogeneity in the 16 fibrosis studies and evidence of heterogeneity in the cirrhosis studies. For significant liver fibrosis (Metavir F2-F4) diagnosis using all of the fibrosis studies, the AUROC curve was 0.84 (95% CI, 0.78 to 0.88). At the recommended FibroTest threshold of 0.48 for a significant liver fibrosis diagnosis, the sensitivity was 60.9%, specificity was 79.9%, and the diagnostic odds ratio was 6.2. For liver cirrhosis (Metavir F4) diagnosis using all of the cirrhosis studies, the AUROC curve was 0.87 (95% CI, 0.85 to 0.9). At the recommended FibroTest threshold of 0.74 for cirrhosis diagnosis, the sensitivity was 61.5%, specificity was 90.8%, and the diagnostic odds ratio was 15.7. While the results demonstrated FibroTest may be useful in excluding a diagnosis of cirrhosis in patients with chronic HBV, the ability to detect significant fibrosis and cirrhosis and exclude significant fibrosis is suboptimal. Xu et al (2014) reported on a systematic review and meta-analysis of studies assessing biomarkers to detect fibrosis in HBV.^28, Included in the analysis of FibroTest were 11 studies (total n=1640 patients). In these 11 studies, AUROC curves ranged from 0.69 to 0.90. Heterogeneity in the studies was statistically significant.

In the Crossan et al (2015) systematic review, 6 studies were included in the pooled estimate of the diagnostic accuracy of FibroTest for significant fibrosis (stage ≥ F2) in HBV.^6, The cutoffs for positivity ranged from 0.40 to 0.48, and the summary sensitivities and specificities were 66% (95% CI, 57% to 75%) and 80% (95% CI, 72% to 86%), respectively. The accuracy for diagnosing cirrhosis in HBV was based on 4 studies with cutoffs for positivity ranging from 0.58 to 0.74; sensitivities and specificities were 74% (95% CI, 25% to 96%) and 90% (95% CI, 83% to 94%), respectively.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are no studies evaluating the effect of this test on outcomes for patients with HBV. Of note, some researchers have suggested that different markers (e.g., HBV FibroSURE) may be needed for this assessment in patients with hepatitis B.^29,

Section Summary: FibroSURE (FibroTest)

FibroSURE is the most widely validated of the noninvasive commercial serum tests. It has been studied in populations with viral hepatitis, NAFLD, and ALD. Although there are established cutoffs for positivity for FibroTest, they were not consistently used in validation studies. The methodologic quality of the validation studies was generally poor. There is no direct evidence that FibroSURE (FibroTest) improves health outcomes. However, there is indirect evidence: FibroTest has been used as an alternative to biopsy to establish trial eligibility in terms of fibrosis or cirrhosis in several RCTs that established the efficacy of HCV treatments.

Multianalyte Serum Assays: Other Than FibroSURE

Clinical Context and Test Purpose

The purpose of noninvasive testing in individuals with chronic liver disease is to detect liver fibrosis so that patients can avoid the potential adverse events of an invasive liver biopsy and receive appropriate treatment. The degree of liver fibrosis is an important factor in determining the appropriate approach for managing patients with liver disease (e.g., hepatitis, ALD, NAFLD).

The question addressed in a portion of the policy is: Does the use of multianalyte serum assays other than FibroSURE for detecting liver fibrosis improve the net health outcome in patients with chronic liver disease?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with chronic liver disease.

Interventions

The tests being considered are multianalyte serum assays for liver function assessment other than FibroSURE. One test, FIBROSpect, consists of measurements of hyaluronic acid, tissue inhibitors of metalloproteinase 1, and α₂-macroglobulin.

Comparators

The following tests and practices are currently being used to diagnose chronic liver disease: liver biopsy, noninvasive radiologic methods, and other multianalyte serum assays.

Outcomes

The general outcomes of interest are test validity, morbid events, and treatment-related morbidity. Follow-up over months to years is of interest to the relevant outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of this test, studies that meet the eligibility criteria are outlined in indication 1.

FIBROSpect II

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Patel et al (2004) investigated the use of serum markers in an initial training set of 294 patients with HCV and further validated the resulting algorithm in a validation set of 402 patients.^30, The algorithm was designed to distinguish between no or mild fibrosis (F0-F1) and moderate-to-severe fibrosis (F2-F4). With the prevalence of F2-F4 disease of 52% and a cutoff value of 0.36, the PPVs and NPVs were 74.3% and 75.8%, respectively. Using a FIBROSpect II cutoff score of 0.42, Christensen et al (2006) reported a sensitivity of 93%, a specificity of 66%, and overall accuracy of 76%, and an NPV of 94% for advanced fibrosis in 136 patients with HCV.^31,

The published studies for this combination of markers continue to focus on test characteristics such as sensitivity, specificity, and accuracy.^32,33,34, In Crossan et al (2015), the summary diagnostic accuracy for detecting significant fibrosis (stage ≥ F2) in 5 studies of HCV with FIBROSpect II, with cutoffs ranging from 42 to 72, was 78% (95% CI, 49% to 93%) and the summary specificity was 71% (95% CI, 59% to 80%).^6,

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

The issues of effect on patient outcomes are similar to those discussed for the FibroSURE (FibroTest in Europe). No studies were identified in the published literature in which the results of the FIBROSpect test were actively used in the management of the patient.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of FIBROSpect has not been established, a chain of evidence supporting the clinical utility of this test for this population cannot be constructed.

Subsection Summary: FIBROSpect II

FIBROSpect II has been studied in populations with HCV. Cutoffs for positivity varied across studies and were not well validated. The methodologic quality of the validation studies was generally poor. There is no direct evidence that FIBROSpect II improves health outcomes.

Other Multianalyte Scoring Systems

Other scoring systems have been developed. For example, the APRI requires only the serum level of AST and the number of platelets and uses a simple nonproprietary formula that can be calculated at the bedside to produce a score for the prediction of fibrosis.^35, Using an optimized cutoff value derived from a training set and validation set of patients with HCV, authors have reported that the NPV for fibrosis was 86% and that the PPV was 88%. In Crossan et al (2015), APRI was frequently evaluated and has been tested in HCV, HBV, NAFLD, and ALD.^6, The summary diagnostic accuracies are in Table 1.

Table 1. Diagnostic Accuracy for APRI

Disease	Metavir Stage	Cutoff	Studies	Sensitivity (95% CI), %	Specificity (95% CI), %
HCV	≥ F2 (significant)	Low: 0.4-0.7	47	82 (77 to 86)	57 (49 to 65)
HCV	≥ F2 (significant)	High: 1.5	36	39 (32 to 47)	92 (89 to 95)
HCV	F4 (cirrhosis)	Low: 0.75-1	24	77 (73 to 81)	78 (74 to 81)
HCV	F4 (cirrhosis)	High: 2	19	48 (41 to 56)	94 (91 to 95)
HBV	≥ F2 (significant)	Low: 0.4-0.6	8	80 (68 to 88)	65 (52 to 77)
HBV	≥ F2 (significant)	High: 1.5	6	37 (22 to 55)	93 (85 to 97)
HBV	F4 (cirrhosis)	Low: 1	4	58 (49 to 66)	76 (70 to 81)
HBV	F4 (cirrhosis)	High: 2	3	24 (8 to 52)	91 (83 to 96)
NAFLD	≥ F3 (significant)	0.5 to 1.0	4	40 (7 to 86)	82 (78 to 60)
NAFLD	F4 (cirrhosis)	0.54 and NA	2	78 (71 to 99)	71 (30 to 93)
ALD	≥ F2 (significant)	Low: 0.5	2	72 (60 to 82)	46 (33 to 60)
ALD	≥ F2 (significant)	High: 1.5	2	54 (42 to 66)	78 (64 to 88)
ALD	F4 (cirrhosis)	High: 2.0	1	40 (22 to 61)	62 (41 to 79)

Adapted from Crossan et al (2015).^6,
ALD: alcoholic liver disease; APRI: aspartate aminotransferase-platelet ratio index; CI: confidence interval; HBV: hepatitis B virus; HCV: hepatitis C virus; NA: not available; NAFLD: nonalcoholic fatty liver disease.

Giannini et al (2006) reported that the use of the AST/ALT ratio and platelet counts in a diagnostic algorithm would have avoided liver biopsy in 69% of their patients and would have correctly identified the absence or presence of significant fibrosis in 80.5% of these cases.^36, In Crossan et al (2015), the cutoffs for the positivity of AST/ALT ratio for diagnosis of significant fibrosis (stage ≥ F2) varied from 0.6 to 1 in 7 studies.^6, Summary sensitivity and specificity were 44% (95% CI, 27% to 63%) and 71% (95% CI, 62% to 78%), respectively. Thirteen studies used a cutoff of 1 to estimate the diagnostic accuracy of cirrhosis with AST/ALT ratio, and summary sensitivity and specificity were 49% (95% CI, 39% to 59%) and 87% (95% CI, 75% to 94%), respectively.

A number of studies have compared HCV FibroSURE (FibroTest) and other noninvasive tests of fibrosis with biopsy using ROC analysis. For example, Bourliere et al (2006) reported on the validation of FibroSURE (FibroTest) and found that, based on ROC analysis, FibroSURE (FibroTest) was superior to APRI for identifying significant fibrosis, with AUROC curves of 0.81 and 0.71, respectively.^37, A prospective multicenter study by Zarksi et al (2012) compared 9 of the best-evaluated blood tests in 436 patients with HCV and found similar performance for HCV FibroSURE (FibroTest), FibroMeter, and HepaScore (ROC curve, 0.84, 0.86, 0.84, respectively).^38, These 3 tests were significantly superior to the 6 other tests, with 70% to 73% of patients considered well classified according to a dichotomized score (F0/F1 vs ≥F2). The number of “theoretically avoided liver biopsies” for the diagnosis of significant fibrosis was calculated to be 35.6% for HCV FibroSURE (FibroTest). To improve diagnostic accuracy, algorithms that combine HCV FibroSURE (FibroTest) with other tests (e.g., APRI) are also being evaluated.^38,39,40,One of these, the sequential algorithm for fibrosis evaluation, combines the APRI and FibroTest. Crossan et al (2015) reported that the algorithm has been assessed in 4 studies of HCV for diagnosing both significant fibrosis (stage ≥ F2) and cirrhosis.^6, Summary sensitivity and specificity for significant fibrosis were estimated to be 100% (95% CI, 100% to 100%) and 81% (95% CI, 80% to 83%), respectively. The summary sensitivity and specificity for cirrhosis were 74% (95% CI, 42% to 92%) and 93% (95% CI, 91% to 94%), respectively.

Rosenberg et al (2004) developed a scoring system based on an algorithm combining hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitors of metalloproteinase 1.^41,This test is manufactured by Siemens Healthcare as the Enhanced Liver Fibrosis (ELF) Test and is presently only available outside of the U. S.^42,The algorithm was developed in a test set of 400 patients with a wide variety of chronic liver diseases and then validated in another 521 patients. The algorithm was designed to discriminate between no or mild fibrosis and moderate-to-severe fibrosis. The NPV for fibrosis was 92%.

The FIB-4 index was developed in a cohort of patients with HCV and is similar to APRI in that it uses a simple nonproprietary formula to produce a score for the prediction of fibrosis, incorporating patient age, AST level, ALT level, and platelet count. In the original cohort studied by Sterling et al (2006)^43,, a low cut-off score of <1.45 had NPV of 90% for advanced fibrosis whereas a high cut-off score >3.25 had a 97% specificity and PPV of 65% for advanced fibrosis. Overall, 70% of patients were stratified <1.45 or >3.25 and represented potential cases that could have avoided liver biopsy with a corresponding diagnostic accuracy of 86%. In a comparative study by Vallet-Pichard et al (2007) in patients with HCV utilizing the same cut-off values, an NPV of 94.7% with a sensitivity of 74.3% and a specificity of 80.1% and a PPV of 82.1% with a specificity of 98.2% and sensitivity of 37.6% were reported.^44, When the diagnostic performance of FIB-4 was compared against FibroTest (FibroSure in the U.S.), the exclusion of severe fibrosis and the detection of severe fibrosis were found to agree between tests in 92.1% and 76.0% of cases, respectively. In more recent work by Angulo et al (2013) in patients with NAFLD for prediction of advanced fibrosis (F3-F4), adjusted cut-offs of 1.30 and 2.67 were used.^45, The corresponding NPV at 1.30 was 83% and PPV at 2.67 was 80%. A liver biopsy was appropriately avoided in 54% of cases.

Sanyal et al (2019) reported on findings of 2, phase 2b, placebo-controlled trials of simtuzumab in NASH in patients with bridging fibrosis (F3; n=217) or compensated cirrhosis (F4; n=258) that assessed patients with liver biopsy and serum biomarker tests, including ELF, APRI, FibroSure/FibroTest, and the FIB-4 index.^46, Laboratory screening was conducted at baseline and at every three months during the course of the trials. The trials were terminated after 96 weeks due to simtuzumab inefficacy, at which point data from treatment groups were combined for analysis. In patients with bridging fibrosis, increased risk of progression to cirrhosis was observed with higher baseline levels of all serum fibrosis tests (p < 0.001). Change in the ELF score over time was also associated with progression to cirrhosis (p<0.001). For a cut-off score of 9.76, progression to cirrhosis had a reported hazard ratio of 4.12 (95% CI: 2.14 to 7.93; p<0.001). For patients with compensated cirrhosis, higher levels of baseline biomarker tests were also associated with liver-related clinical events in 19% of patients, such as ascites, hepatic encephalophathy, newly diagnosed varices, esophageal variceal bleed, increase in Child-Pugh and/or MELD score, or death ( p<0.001 to 0.006). While the manufacturer of the test differentiates moderate from severe fibrosis with a cut-off ELF score of 9.8, current National Institute for Health and Care Excellence guidelines for NAFLD recommend reserving a diagnosis of advanced fibrosis to NAFLD patients with an ELF score of 10.51 or greater, limiting the clinical significance of these findings.^47, Furthermore, serum fibrosis test results were not directly used in patient management in the simtuzumab trials.

Section Summary: Multianalyte Serum Assays Other Than FibroSURE

For multianalyte serum assays other than FibroSURE (e.g., FIBROSpect II, ELF), there are a number of studies; however, all studies have included varying cutoffs, some of which were standardized and others not validated. Cut-off thresholds have often been modified over time, may be specific to certain patient populations, and in some cases, guideline recommendations differ from cut-offs designated by manufacturers and those utilized in studies. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. There is no direct evidence that other multianalyte serum assays improve health outcomes and a chain of evidence cannot be constructed given the inadequate data on clinical validity. Other multianalyte serum tests (e.g., APRI, FIB-4) lack data on clinical validity and utility. There does not appear to be evidence of incremental benefit over clinical assessment using the individual laboratory assay components.

Noninvasive Imaging: Transient Elastography

Clinical Context and Test Purpose

The purpose of noninvasive testing in individuals with chronic liver disease is to detect liver fibrosis so that patients can avoid the potential adverse events of an invasive liver biopsy and receive appropriate treatment. The degree of liver fibrosis is an important factor in determining the appropriate approach for managing patients with liver disease (e.g., hepatitis, ALD, NAFLD).

The question addressed in this portion of the policy is: Does the use of transient elastography for detecting liver fibrosis improve the net health outcome in patients with chronic liver disease?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with chronic liver disease.

Interventions

The therapy being considered is transient elastography (e.g., FibroScan).

Comparators

The following tests and practices are currently being used to diagnose chronic liver disease: liver biopsy, other noninvasive radiologic methods, and multianalyte serum assays.

Outcomes

The general outcomes of interest are test validity, morbid events, and treatment-related morbidity. Follow-up over months to years is of interest to the relevant outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of this test, studies that meet the eligibility criteria are outlined in indication 1.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

There is extensive literature on the use of transient elastography to gauge liver fibrosis and cirrhosis. Summaries of systematic reviews are shown in Tables 2 and 3. Brener (2015) performed a health technology assessment summarizing many of the systematic reviews below.^48, The assessment focused on reviews of the diagnostic accuracy and effect on patient outcomes of transient elastography for liver fibrosis in patients with HCV, HBV, NAFLD, ALD, or cholestatic diseases. Fourteen systematic reviews of transient elastography with biopsy reference standard shown below were included in the Brener assessment, summarizing more than 150 primary studies.^{49,50,51,52,53,54,55,56,57,58,59,60,61,} There was variation in the underlying cause of liver disease and the cutoff values of transient elastography stiffness used to define Metavir stages in the systematic reviews. There did not appear to be a substantial difference in diagnostic accuracy for one disease over any other. The reviews demonstrated that transient elastography has good diagnostic accuracy compared with biopsy for the assessment of liver fibrosis and steatosis.

Crossan et al (2015) found that FibroScan was the noninvasive liver test most assessed in validation studies across liver diseases (37 studies in HCV, 13 in HBV, 8 in NAFLD, 6 in ALD).^6, Cutoffs for positivity for fibrosis staging varied between diseases and were frequently not prespecified or validated: HCV, 5.2 to 10.1 kilopascal (kPa) in the 37 studies for Metavir stages ≥ F2; HBV, 6.3 to 8.9 kPa in 13 studies for stages ≥ F2; NAFLD, 7.5 to 10.4 kPa in 8 studies for stages ≥ F3; ALD, 11.0 to 12.5 in 4 studies for stages ≥ F3. Summary sensitivities and specificities by the disease are shown in Table 3. The overall sensitivity and specificity for cirrhosis including all diseases (65 studies; cutoffs range, 9.2-26.5 kPa) were 89% (95% CI, 86% to 91%) and 89% (95% CI, 87% to 91%), respectively. The rate of uninterpretable results, when reported, with FibroScan (due to <10 valid measurements; success rate, <60%; interquartile range, >30%) was 8.5% in HCV and 9.6% in NAFLD.

Table 2. Transient Elastography Systematic Review Characteristics

Study	Dates	Studies	N	Population
Bota et al (2013)49,	To May 2012	13	1163	Chronic hepatitis
Chon et al (2012)50,	2002 to Mar 2011	18	2772	HBV
Crossan et al (2015)6,	1998 to Apr 2012	66	NR	HCV, HBV, NAFLD, ALD
Friedrich-Rust et al (2008)51,	2002 to Apr 2007	50	11,275	All causes of liver disease
Friedrick-Rust et al (2012)62,	To Oct 2010	8	518	All causes of liver disease
Geng et al (2016)63,	To Jan 2015	57	10,569	Multiple causes of liver disease
Jiang et al (2018)64,	To Dec 2017	11	1735	NAFLD
Kwok et al (2014)52,	To Jun 2013	22	1047	NAFLD
Li et al (2016)65,	Jan 2003 to Nov 2014	27	4386	HBV
Njei et al (2016)66,	To Jan 2016	6	756	HCV/HIV coinfection
Pavlov et al (2015)67,	To Aug 2014	14	834	ALD
Poynard et al (2008)53,	1991 to 2008	66	NR	All causes of liver disease
Poynard et al (2011)54,	Feb 2001 to Dec 2010	18	2714	HBV
Shaheen et al (2007)55,	Jan 1997 to Oct 2006	12	1981	HCV
Shi et al (2014)56,	To May 2013	9	1771	All causes of steatosis
Steadman et al (2013)57,	2001 to Jun 2011	64	6028	HCV, HBV, NAFLD, CLD, liver transplant
Stebbing et al (2010)58,	NR, prior to Feb 2009	22	4625	All causes of liver disease
Talwalkar et al (2007)59,		9	2083	All causes of liver disease
Tsochatzis et al (2011)60,	To May 2009	40	7661	All causes of liver disease
Tsochatzis et al (2014)61,	1998 to Apr 2012	302	NR	HCV, HBV, ALD, NAFLD
Xu et al (2015)68,	To Dec 2013	19	3113	HBV

ALD: alcoholic liver disease; CLD: chronic liver disease; HBV: hepatitis B virus; HCV: hepatitis C virus; NAFLD: nonalcoholic fatty liver disease; NR: not reported.

Table 3. Transient Elastography Systematic Reviews Diagnostic Accuracy Results

		Significant Fibrosis (i.e., Metavir Stages F2-F4)		Cirrhosis (i.e., Metavir Stage F4)
Study	Population	Studies/ Sample Size	AUROC (95% CI) Sensitivity (95% CI) Specificity (95% CI)	Studies/ Sample Size	AUROC (95% CI) Sensitivity (95% CI) Specificity (95% CI)
Bota et al (2013)49,	Multiple diseases	10/1016	0.87 (0.83 to 0.89) 78% (72% to 83%) 84% (75% to 90%)	13/1163	0.93 (0.91 to 0.95) 89% (80% to 94%) 87% (82% to 91%)
	HCV			4/NR	NR 92% (78% to 97%) 86% (82% to 90%)
Chon et al (2012)50,	Chronic HBV	12/2000	0.86 (0.86 to 0.86) 74.3% (NR) 78.3% (NR)	16/2614	0.93 (0.93 to 0.93) 84.6% (NR) 81.5% (NR)
Crossan et al(2015)6,	HCV	37/NR	NR 79% (74% to 84%) 83% (77% to 88%)	36/NR	NR 89% (84% to 92%) 91% (89% to 93%)
	HBV	13/NR	NR 71% (62% to 78%) 84% (74% to 91%)	19/NR	NR 86% (79% to 91%) 85% (78% to 89%)
	NAFLD			4/NR	NR 96% (83% to 99%) 89% (85% to 92%)
	ALD	1/NR	NR 81% (70% to 88%) 92% (76% to 98%)	4/NR	NR 87% (64% to 96%) 82% (67% to 91%)
Friedrich- Rust (2008)51,	Multiple diseases	25/3685	0.84 (0.82 to 0.86) NR NR	25/4557	0.94 (0.93 to 0.95) NR NR
	HCV	NR	0.84 (0.80 to 0.86) NR NR
Friedrick- Rust et al(2012)62,	No summary statistics reported for transient elastography
Geng et al(2016)63,	Multiple diseases				0.93 (NR) 81% (79% to 83%) 88% (87% to 89%)
Jiang et al (2018)64,	NAFLD	10/NR	0.85 (0.82 to 0.88) 77% (70% to 84%) 80% (74% to 84%)	11/NR	0.96 (0.93 to 0.97) 90% (73% to 97%) 91% (87% to 94%)
Kwok et al(2014)52,	NAFLD	7/800	0.83 (0.79 to 0.87) 0.79 (0.72 to 0.84) 0.75 (0.71 to 0.79)	57/10,569	0.96 (0.94 to 0.99) 92% (82% to 97%) 92% (86% to 98%)
Li et al (2016)65,	HBV	19/NR	0.88 (0.85 to 0.91) 81% (76% to 85%) 82% (71% to 87%)	24/NR	0.93 (0.91 to 0.95) 86% (82% to 90%) 88% (84% to 90%)
Njei et al (2016)66,	HCV/HIV	6/756	NR 97% (82% to 91%) 64% (45% to 79%)	6/756	NR 90% (74% to 91%) 87% (80% to 92%)
Pavlov et al(2015)67,	ALD	7/338	NR 94% (86% to 97%) 89% (76% to 95%)	7/330	NR 95% (87% to 98%) 71% (56% to 82%)
Poynard et al(2008)53,	No summary statistics reported for transient elastography
Poynard et al(2011)54,	HBV	4/NR	0.84 (0.78 to 0.89) NR NR	NR	0.93 (0.87 to 0.99) NR NR
Shaheen et al(2007)55,	HCV	4/NR	0.84 (0.78 to 0.89) NR NR	NR	0.93 (0.87 to 0.99) NR NR
Shi et al(2014)56,	No summary statistics reported. Concluded that transient elastography controlled attenuation parameter has good sensitivity and specificity for diagnosing steatosis, but it has limited utility
Steadman et al (2013)57,	Multiple diseases	45/NR	0.88 (0.84 to 0.90) 80% (76% to 83%) 81% (77% to 85%)	49/NR	0.94 (0.91 to 0.96) 86% (82% to 89%) 89% (87% to 91%)
	HBV	5/710	0.81 (0.78 to 0.84) 77% (68% to 84%) 72% (55% to 85%)	8/1092	0.86 (0.82 to 0.89) 67% (57% to 75%) 87% (83% to 91%)
	HCV	13/2732	0.89 (0.86 to 0.91) 76% (61% to 86%) 86% (77% to 92%)	12/2887	0.94 (0.92 to 0.96) 85% (77% to 91%) 91% (87% to 93%)
	NAFLD	5/630	0.78 (0.74 to 0.82) 77% (70% to 83%) 75% (70% to 79%)	4/469	0.96 (0.94 to 0.97) 92% (77% to 98%) 95% (88% to 98%)
Stebbing et al(2010)58,	Multiple diseases	17/3066	NR 72% (71% to 72%) 82% (82% to 83%)	17/4052	NR 84% (84% to 85%) 95% (94% to 95%)
Talwalkar et al(2007)59,	Multiple diseases	7/>1100	0.87 (0.83 to 0.91) 70% (67% to 73%) 84% (80% to 88%)	9/2083	0.96 (0.94 to 0.98) 87% (84% to 90%) 91% (89% to 92%)
Tsochatzis et al(2011)60,	Multiple diseases	31/5919	NR 79% (74% to 82%) 78% (72% to 83%)	30/6530	NR 83% (79% to 86%) 89% (87% to 91%)
	HCV	14/NR	NR 78% (71% to 84%) 80% (71% to 86%)	11/NR	NR 83% (77% to 88%) 90% (87% to 93%)
	HBV	4/NR	NR 84% (67% to 93%) 78% (68% to 85%)	6/NR	NR 80% (61% to 91%) 86% (82% to 94%)
Tsochatzis et al(2014)61,	HCV	37/NR	0.87 (0.83 to 0.90) 79% (74% to 84%) 83% (77% to 88%)	36/NR	0.96 (0.94 to 0.97) 89% (84% to 92%) 91% (89% to 93%)
	HBV	13/NR	0.83 (0.76 to 0.90) 71% (62% to 78%) 84% (74% to 91%)	13/NR	0.92 (0.89 to 0.96) 86% (79% to 91%) 85% (78% to 89%)
	NAFLD			4/NR	0.96 (0.94 to 0.99) 96% (83% to 99%) 89% (85% to 92%)
	ALD			6/NR	0.90 (0.87 to 0.94) 86% (76% to 92%) 83% (74% to 89%)
Xu et al(2015)68,	HBV	14/2318	0.82 (0.78 to 0.86) NR NR	18/2996	0.91 (0.89 to 0.93) NR NR

ALD: alcoholic liver disease; AUROC: area under the receiver operating characteristic curve; CI: confidence interval; HBV: hepatitis B virus; HCV: hepatitis C virus; NAFLD: nonalcoholic fatty liver disease; NR: not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are currently no published studies that directly demonstrate the effect of transient elastography (e.g., FibroScan) on patient outcomes.

FibroScan is used extensively in practice to make management decisions. In addition, FibroScan was used as an alternative to biopsy to diagnose fibrosis or cirrhosis to establish trial eligibility in several trials (ION-1,-3; VALENCE; ASTRAL-2, -3, -4) that confirmed the efficacy of HCV treatments.^{15,16,17,18,19,20,} For example, in the VALENCE trial, cirrhosis could be defined by liver biopsy or a confirmatory FibroTest or FibroScan result at 12.5 kPa or greater. In VALENCE, FibroScan was used to determine cirrhosis in 74% of the participants. In a retrospective, multicenter analysis of 7256 chronic HCV patients by Abdel Alem et al (2019), both transient elastography and FIB-4 were found to be predictors of treatment failure to sofosbuvir-based treatment regimens with an NPV of 95%.^69,

Section Summary: Transient Elastography (FibroScan)

Transient elastography (FibroScan) is the most widely validated of the noninvasive methods. FibroScan has been studied in populations with viral hepatitis, NAFLD, and ALD. FibroScan validation studies have suggested that it can provide good detection of significant fibrosis and good-to-excellent detection of cirrhosis compared with liver biopsy for HCV and HBV. There are limited data on NAFLD and ALD. There are no established or validated cutoffs, and the quality of the validation studies was generally not high. Failures of the test are not uncommon, particularly for those with high body mass index; however, failures were frequently missed in analyses of the validation studies. Newer more sensitive probes may lessen this limitation. There is no direct evidence that FibroScan improves health outcomes. However, FibroScan has been used as an alternative to biopsy to diagnose fibrosis or cirrhosis to establish trial eligibility in several RCTs that established the efficacy of HCV treatments.

Other Noninvasive Imaging

The following noninvasive imaging types are evaluated in this section: magnetic resonance elastography (MRE), ARFI imaging (e.g., Acuson S2000), and real-time tissue elastography (RTE; e.g., HI VISION Preirus).

Clinical Context and Test Purpose

The purpose of noninvasive testing in individuals with chronic liver disease is to detect liver fibrosis so that patients can avoid the potential adverse events of an invasive liver biopsy and receive appropriate treatment. The degree of liver fibrosis is an important factor in determining the appropriate approach for managing patients with liver disease (e.g., hepatitis, ALD, NAFLD).

The question addressed in this portion of the policy is: Does the use of noninvasive imaging other than transient elastography for detecting liver fibrosis improve the net health outcome in patients with chronic liver disease?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with chronic liver disease.

Interventions

The tests being considered are noninvasive radiologic methods other than transient elastography for liver fibrosis measurement (e.g., MRE, ARFI imaging, RTE).

Comparators

The following tests and practices are currently being used to diagnose chronic liver disease: liver biopsy, other noninvasive radiologic methods, and multianalyte serum assays.

Outcomes

The general outcomes of interest are test validity, morbid events, and treatment-related morbidity. Follow-up over months to years is of interest to the relevant outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of this test, studies that meet the eligibility criteria are outlined in indication 1.

ARFI Imaging

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Tables 4 and 5 summarize the characteristics and results of systematic reviews that have assessed the diagnostic accuracy of ARFI imaging.

Table 4. Characteristics of Systematic Reviews Assessing Acoustic Radiation Force Impulse Imaging

Study	Dates	Studies	N	Population
Bota et al (2013)49,	To May 2012	6	518	Chronic hepatitis
Crossan et al (2015)6,	1998 to Apr 2012	4	Not reported	Hepatitis C virus
Guo et al (2015)70,	To Jun 2013	15	2128	Multiple diseases
Hu et al (2017)71,	To Jul 2014	fz7	723	Nonalcoholic fatty liver disease
Jiang et al (2018)64,	To Dec 2017	9	982	Nonalcoholic fatty liver disease
Liu et al (2015)72,	To Apr 2016	23	2691	Chronic hepatitis B or C
Nierhoff et al (2013)73,	2007 to Feb 2012	36	3951	Multiple diseases

Table 5. Results of Systematic Reviews Assessing the Diagnostic Accuracy of Acoustic Radiation Force Impulse Imaging

		Significant Fibrosis (i.e., Metavir Stages F2-F4)		Cirrhosis (i.e., Metavir Stage F4)
Study	Population	Studies/ Sample Size	AUROC (95% CI) Sensitivity (95% CI) Specificity (95% CI)	Studies/ Sample Size	AUROC (95% CI) Sensitivity (95% CI) Specificity (95% CI)
Bota et al (2013)49,	Chronic hepatitis	6/518	0.88 (0.83 to 0.93) NR NR		0.92 (0.87 to 0.98) NR NR
Crossan et al (2015)6,	HCV	4/NR	NR 85% (69% to 94%) 89% (72% to 97%)
Guo et al (2015)70,	Multiple diseases	13/NR	NR 76% (73% to 78%) 80% (77% to 83%)	14/NR	NR 88% (84% to 91%) 80% (81% to 84%)
Hu et al (2017)71,	HBV, HCV	15/NR	88% (85% to 91%) 75% (69% to 78%) 85% (81% to 89%)
Jiang et al (2018)64,	NAFLD	6/NR	0.86 (0.83 to 0.89) 70% (59% to 79%) 84% (79% to 88%)	7/NR	0.95 (0.93 to 0.97) 89% (60% to 98%) 91% (82% to 95%)
Liu et al (2015)72,	NAFLD	7/723	NR 80% (76% to 84%) 85% (81% to 89%)
Nierhoff et al (2013)73,	Multiple diseases	26/NR	0.83 (0.80 to 0.86) NR NR	27/NR	0.91 (0.89 to 0.93) NR NR

AUROC: area under the receiver operating characteristic curve; CI: confidence interval; HBV: hepatitis B virus; HCV: hepatitis C virus; NAFLD: nonalcoholic fatty liver disease; NR: not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are currently no published studies that directly demonstrate the effect of ARFI imaging on patient outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of ARFI imaging has not been established, a chain of evidence supporting the clinical utility of this test for this population cannot be constructed.

Subsection Summary: ARFI Imaging

The use of ARFI imaging has been evaluated in viral hepatitis and NAFLD. Moreover, many have noted that ARFI imaging has potential advantages over FibroScan - it can be implemented on a standard ultrasound machine, may be more applicable for assessing complications such as ascites and may be more applicable in obese patients. ARFI imaging appears to have similar diagnostic accuracy to FibroScan, but there are fewer data available on performance characteristics. Validation studies have used varying cutoffs for positivity.

Magnetic Resonance Elastography

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Tables 6 and 7 summarize the characteristics and results of systematic reviews that have assessed the diagnostic accuracy of MRE. MRE has been studied primarily in hepatitis and NAFLD.

Table 6. Characteristics of Systematic Reviews Assessing Magnetic Resonance Elastography

Study	Dates	Studies	N	Population
Crossan et al (2015)6,	1998 to Apr 2012	3	Not reported	Chronic liver disease
Guo et al (2015)70,	To Jun 2013	11	982	Multiple diseases
Singh et al (2015)74,	2003 to Sep 2013	12	697	Chronic liver disease
Singh et al (2016)75,	To Oct 2014	9	232	Nonalcoholic fatty liver disease
Xiao et al (2017)76,	To 2016	5	628	Nonalcoholic fatty liver disease

Table 7. Results of Systematic Reviews Assessing the Diagnostic Accuracy of Magnetic Resonance Elastography

		Significant Fibrosis (i.e., Stages F2-F4)		Cirrhosis (i.e., Stage F4)
Study	Population	Studies/ Sample Size	AUROC (95% CI) Sensitivity (95% CI) Specificity (95% CI)	Studies/ Sample Size	AUROC (95% CI) Sensitivity (95% CI) Specificity (95% CI)
Crossan et al (2015)6,	Chronic liver disease	3/NR	NR 94% (13% to 100%) 92% (72% to 98%)
Guo et al (2015)70,	Multiple diseases	9/NR	NR 87% (84% to 90%) 94% (91% to 97%)		NR 93% (88% to 96%) 91% (88% to 93%)
Singh et al (2015)74,	Chronic hepatitis	12/697	0.84 (0.76 to 0.92) 73% (NR) 79% (NR)	12/697	0.92 (0.90 to 0.94) 91% (NR) 81% (NR)
Singh et al (2016)75,	NAFLD	9/232	0.87 (0.82 to 0.93) 79% (76% to 90%) 81% (72% to 91%)	9/232	0.91 (0.76 to 0.95) 88% (82% to 100%) 87% (77% to 97%)
Xiao et al (2017)76,	NAFLD	3/384	0.88 (0.83 to 0.92) 73.2% (65.7% to 87.3%) 90.7% (85.0% to 95.7%)	3/384	0.92 (0.80-1.00) 86.6% (80.0% to 90.9%) 93.4% (91.4% to 94.5%)

AUROC: area under the receiver operating characteristic curve; CI: confidence interval; NAFLD: nonalcoholic fatty liver disease; NR: not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are currently no published studies that directly demonstrate the effect of MRE on patient outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of MRE has not been established, a chain of evidence supporting the clinical utility of this test for this population cannot be constructed.

Subsection Summary: MRE

MRE has a high success rate and is highly reproducible across operators and time. The diagnostic accuracy also appears to be high. In particular, MRE has high diagnostic accuracy for the detection of fibrosis in NAFLD, independent of body mass index and degree of inflammation. However, further validation is needed to determine standard cutoffs and confirm performance characteristics because confidence intervals for estimates are wide. MRE is not widely available.

Real-Time Tissue Elastography (HI VISION 15 Preirus)

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Kobayashi et al (2015) published results of a meta-analysis assessing RTE for staging liver fibrosis.^77, They selected 15 studies (total n=1626 patients) published through December 2013, including patients with multiple liver diseases and healthy adults. A bivariate random-effects model was used to estimate summary sensitivity and specificity. The summary AUROC, sensitivity, and specificity were 0.69 (precision NR), 79% (95% CI, 75% to 83%), and 76% (95% CI, 68% to 82%) for detection of significant fibrosis (stage ≥ F2) and 0.72 (precision NR), 74% (95% CI, 63% to 82%), and 84% (95% CI, 79% to 88%) for detection of cirrhosis, respectively. Reviewers found evidence of heterogeneity due to differences in study populations, scoring methods, and cutoffs for positivity. They also found evidence of publication bias based on funnel plot asymmetry.

Hong et al (2014) reported on the results of a meta-analysis evaluating RTE for staging fibrosis in multiple diseases.^78, Thirteen studies (total n=1347 patients) published between April 2000 and April 2014 that used a liver biopsy or transient elastography as the reference standard were included. Different quantitative methods were used to measure liver stiffness in the included studies: Liver Fibrosis Index (LFI), Elasticity Index, elastic ratio 1 (ER1), and elastic ratio 2. For predicting significant fibrosis (stage ≥ F2), the pooled sensitivities for LFI and ER1 were 78% (95% CI, 70% to 84%) and 86% (95% CI, 80% to 90%), respectively. The specificities were 63% (95% CI, 46% to 78%) and 89% (95% CI, 83% to 94% and the AUROCs were 0.79 (95% CI, 0.75 to 0.82) and 0.94 (95% CI, 0.92 to 0.96), respectively. For predicting cirrhosis (stage F4), the pooled sensitivities of LFI, ER1, and elastic ratio 2 were 79% (95% CI, 61% to 91%), 96% (95% CI, 87% to 99%), and 79% (95% CI, 61% to 91%), respectively. The specificities were 88% (95% CI, 81% to 93%) for LFI, 89% (95% CI, 83% to 93%) for ER1, and 88% (95% CI, 81% to 93%) for elastic ratio 2, and the AUROCs were 0.85 (95% CI, 0.81 to 0.87), 0.93 (95% CI, 0.94 to 0.98), and 0.92 (95% CI NR), respectively. Pooled estimates for Elasticity Index were not performed due to insufficient data.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are currently no published studies that directly demonstrate the effect of RTE on patient outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of RTE has not been established, a chain of evidence supporting the clinical utility of this test for this population cannot be constructed.

Subsection Summary: RTE

RTE has been evaluated in multiple diseases with varying scoring methods and cutoffs. Although data are limited, the accuracy of RTE appears to be similar to FibroScan for the evaluation of significant liver fibrosis, but less accurate for the evaluation of cirrhosis. However, there was evidence of publication bias in the systematic review and the diagnostic accuracy may be overestimated.

Section Summary: Noninvasive Radiological Methods Other Than Transient Elastography

The available studies have suggested that other radiologic methods (ARFI, MRE, RTE) may have similar performance for detecting significant fibrosis or cirrhosis. However, the studies frequently included varying cutoffs not prespecified or validated. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. There is no direct evidence that other noninvasive radiologic methods improve health outcomes and an indirect chain cannot be constructed due to the lack of sufficient evidence on clinical validity.

Summary of Evidence

Multianalyte Serum Assays

For individuals who have chronic liver disease who receive FibroSURE serum panels, the evidence includes systematic reviews of more than 30 observational studies (>5000 patients). The relevant outcomes are test validity, morbid events, and treatment-related morbidity. FibroSURE has been studied in populations with viral hepatitis, NAFLD, and ALD. There are established cutoffs, although they were not consistently used in validation studies. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. However, for the purposes of deciding whether a patient has severe fibrosis or cirrhosis, FibroSURE results provide data sufficiently useful to determine therapy. Specifically, FibroSURE has been used as an alternative to biopsy to establish eligibility regarding the presence of fibrosis or cirrhosis in several randomized controlled trials that showed the efficacy of HCV treatments, which in turn demonstrated the test can identify patients who would benefit from therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic liver disease who receive multianalyte serum assays for liver function assessment other than FibroSURE, the evidence includes systematic reviews of observational studies. The relevant outcomes are test validity, morbid events, and treatment-related morbidity. Studies have frequently included varying cutoffs, some of which were standardized and others not validated. Cut-off thresholds have often been modified over time, may be specific to certain patient populations, and in some cases, guideline recommendations differ from cut-offs designated by manufacturers and those utilized in studies. Other multianalyte serum tests (e.g., APRI, FIB-4) lack data on clinical validity and utility. There does not appear to be evidence of incremental benefit over clinical assessment using the individual laboratory assay components. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. There is no direct evidence that other multianalyte serum assays improve health outcomes; further, it is not possible to construct a chain of evidence for clinical utility due to the lack of sufficient evidence on clinical validity. The evidence is insufficient to determine the effects of the technology on health outcomes.

Noninvasive Imaging

For individuals who have chronic liver disease who receive transient elastography, the evidence includes many systematic reviews of more than 50 observational studies (>10000 patients). The relevant outcomes are test validity, morbid events, and treatment-related morbidity. Transient elastography (FibroScan) has been studied in populations with viral hepatitis, NAFLD, and ALD. There are varying cutoffs for positivity. Failures of the test are not uncommon, particularly for those with high body mass index, but these failures often went undetected in analyses of the validation studies. Given these limitations and the imperfect reference standard, it can be difficult to interpret performance characteristics. However, for the purposes of deciding whether a patient has severe fibrosis or cirrhosis, the FibroScan results provide data sufficiently useful to determine therapy. In fact, FibroScan has been used as an alternative to biopsy to establish eligibility regarding the presence of fibrosis or cirrhosis in the participants of several RCTs. These trials showed the efficacy of HCV treatments, which in turn demonstrated that the test can identify patients who would benefit from therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic liver disease who receive noninvasive radiologic methods other than transient elastography for liver fibrosis measurement, the evidence includes systematic reviews of observational studies. The relevant outcomes are test validity, morbid events, and treatment-related morbidity. Other radiologic methods (e.g., MRE, RTE, ARFI imaging) may have similar performance for detecting significant fibrosis or cirrhosis. Studies have frequently included varying cutoffs not prespecified or validated. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. There is no direct evidence that other noninvasive radiologic methods improve health outcomes; further, it is not possible to construct a chain of evidence for clinical utility due to the lack of sufficient evidence on clinical validity. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 3 physician specialty societies and 3 academic medical centers while this policy was under review in 2015 Most reviewers considered noninvasive techniques for the evaluation and monitoring of chronic liver disease to be investigational, both individually and in combination.

Practice Guidelines and Position Statements

Nonalcoholic Fatty Liver Disease

American Gastroenterological Association et al

The practice guidelines on the diagnosis and management of NAFLD, developed by the American Gastroenterological Association, the American Association for the Study of Liver Diseases, and the American College of Gastroenterology (2018) stated that “NFS [NAFLD fibrosis score] or FIB-4 [Fibrosis-4] index are clinically useful tools for identifying NAFLD patients with higher likelihood of having bridging fibrosis (stage 3) or cirrhosis (stage 4).”^79, It also cited VCTE [vibration-controlled transient elastography] and MRE [magnetic resonance elastography] as “clinically useful tools for identifying advanced fibrosis in patients with NAFLD.”

National Institute for Health and Care Excellence

The NICE (2016) published guidance on the assessment and management of NAFLD.^80, The guidance did not reference elastography. The guidance recommended the enhanced liver fibrosis test to test for advanced liver fibrosis, utilizing a cut-off enhanced liver fibrosis score of 10.51.

American Gastroenterological Association Institute

The American Gastroenterological Association Institute (2017) published guidelines on the role of elastography in chronic liver disease. The guidelines indicated that, in adults with NAFLD, VCTE has superior diagnostic sensitivity and specificity for diagnosing cirrhosis than the APRI or FIB-4 tests(very low quality of evidence).^79, Moreover, the guidelines stated that, in adults with NAFLD, magnetic resonance-guided elastography has little or no increased diagnostic accuracy for identifying cirrhosis compared with VCTE in patients who have cirrhosis, and has higher diagnostic accuracy than VCTE in patients who do not have cirrhosis (very low quality of evidence).

Hepatitis B and C Viruses

National Institute for Health and Care Excellence

The NICE (2013) published guidance on the management and treatment of patients with hepatitis B.^80, The guidance recommended offering transient elastography as the initial test in adults diagnosed with chronic hepatitis B, to inform the antiviral treatment decision (see Table 8).

Table 8. Antiviral Treatment Recommendations by Transient Elasticity Score

Transient Elasticity Score	Antiviral Treatment
>11 kPa	Offer antiviral treatment
6-10 kPa	Offer liver biopsy to confirm fibrosis level prior to offering antiviral treatment
<6 kPa plus abnormal (ALT)	Offer liver biopsy to confirm fibrosis level prior to offering antiviral treatment
<6 plus normal ALT	Do not offer antiviral treatment

ALT: alanine aminotransferase; kPa: kilopascal.

As of September 2016, the NICE had placed a pause on the development of the guidance on hepatitis C, citing instability and costs in the availability of treatments for the condition.

American Association for the Study of Liver Diseases and Infectious Diseases Society of America

The American Association for the Study of Liver Diseases and Infectious Diseases Society of America (2018) guidelines for testing, managing, and treating hepatitis C virus (HCV) recommended that, for counseling and pretreatment assessment purposes, the following should be completed:

“Evaluation for advanced fibrosis using liver biopsy, imaging, and/or noninvasive markers is recommended in all persons with HCV infection to facilitate an appropriate decision regarding HCV treatment strategy and determine the need for initiating additional measures for the management of cirrhosis (e.g., hepatocellular carcinoma screening).
Rating: Class I, Level A [evidence and/or general agreement; data derived from multiple randomized trials, or meta-analyses]”^81,

The guidelines noted that there are several noninvasive tests to stage the degree of fibrosis in patients with HCV. Tests included indirect serum biomarkers, direct serum biomarkers, and VCTE. The guidelines asserted that no single method is recognized to have high accuracy alone and careful interpretation of these tests is required.

American Gastroenterological Association Institute

Guidelines published by the American College of Gastroenterology Institute (2017) on the role of elastography in chronic liver disease indicated that, in adults with chronic hepatitis B virus and chronic HCV, VCTE has superior diagnostic performance for diagnosing cirrhosis than the APRI and FIB-4 tests (moderate quality of evidence for HCV, low quality of evidence for hepatitis B virus).^79, In addition, the guidelines stated that, in adults with HCV, magnetic resonance-guided elastography has little or no increased diagnostic accuracy for identifying cirrhosis compared with VCTE in patients who have cirrhosis, and has lower diagnostic accuracy than VCTE in patients who do not have cirrhosis (very low quality of evidence).

Chronic Liver Disease

American College of Radiology

The American College of Radiology (2017) appropriateness criteria rated 1-dimensional transient elastography as a 7 (usually appropriate) for the diagnosis of liver fibrosis in patients with chronic liver disease.^82, The criteria noted, “This procedure is less reliable in diagnosing liver fibrosis and cirrhosis in patients with obesity or ascites.”

European Association for the Study of Liver Disease et al

The European Association for the Study of Liver Disease and the Asociacion Latinoamericana para el Estudio del Higado (2015) convened a panel of experts to develop clinical practice guidelines on the use of noninvasive tests to evaluate liver disease severity and prognosis.^83, The publication summarized the advantages and disadvantages of noninvasive techniques (serum biomarkers, imaging techniques). Table 9 summarized the joint recommendations for serum biomarkers and transient elastography.

Table 9. Recommendations for Serum Biomarkers and Transient Elastography

Biomarkers	QOE	SOR
“Serum biomarkers can be used in clinical practice due to high applicability (>95%) and good reproducibility.”	High	Strong
“TE can be considered the non-invasive standard for the measure of LS”	High	Strong
“Serum biomarkers are well-validated for chronic viral hepatitis…. They are less well-validated for NAFLD not validated in other chronic kidney diseases.”	High	Strong
"For the diagnosis of significant fibrosis a combination of tests with concordance may provide the highest diagnostic accuracy”	High	Weak
“All HCV patients should be screened to exclude cirrhosis by TE [or]… serum biomarkers.…”	High	Strong
“Non-invasive assessment including serum biomarkers or TE can be used as first-line procedure for the identification of patients at low risk of severe fibrosis/cirrhosis”	High	Strong
“Follow-up assessment by either serum biomarkers or TE for progression of liver fibrosis should be used for NAFLD patients at a 3-year interval”	Moderate	Strong

HCV: hepatitis C virus; LS: liver stiffness; NAFLD: nonalcoholic fatty liver disease; QOE: quality of evidence; SOR: strength of recommendation; TE: transient elastography.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 10.

Table 10. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03938246a	A Phase 2, Multi-Center, Single-Blind, Randomized, Placebo-Controlled Study of TVB 2640 in Subjects With Non-Alcoholic Steatohepatitis	117	May 2020 (recruiting)
NCT0330165a	A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Pemafibrate in Patients With Nonalcoholic Fatty Liver Disease	100	May 2020 (recruiting)
NCT03308916a	Screening At-risk Populations for Hepatic Fibrosis With Non-invasive Markers (SIPHON)	4000	Oct 2032 (recruiting)
NCT02037867	The Stratification of Liver Disease in the Community Using Fibrosis Biomarkers	2000	May 2033 (recruiting)
Unpublished
NCT02569567	Applicability, Reliability and Accuracy for Staging Hepatic Fibrosis: Comparison of Smart-Shear Wave Elastography and Transient Elastography	105	Jun 2016 (unknown)
NCT01789008	Interest of Transient Elastography in the Determination of Advanced Fibrosis in Alcoholic Liver Disease in Alcoholic Patients in Weaning.	300	Aug 2017 (completed)

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Noninvasive Techniques for the Evaluation and Monitoring of Patients with Chronic Liver Disease
Multianalyte Assays with Algorithmic Analysis for the Evaluation and Monitoring of Patients with Chronic Liver Disease
FibroSure
HCV FibroSure
ASH FibroSure
NASH FibroSure
FibroSpect
Liver Fibrosis, Serum Markers for
Serum Markers, Liver Fibrosis
FibroScan
Transient Elastography
Magnetic Resonance Elastography
MRE
ARFI
Acuson S2000
Real-Time Tissue Elastography
Real Time Tissue Elastography
Hi Vision Preirus
AIXPLORER Ultrasound System
ElastQ Imaging Shear Wave Elastography

References:
1. Siemens Healthineers. Press Releases: FDA Grants Breakthrough Device Designation to Siemens Healthineers Enhanced Liver Fibrosis Test. November 8, 2018. https://www.siemens-healthineers.com/en-us/press-room/press-releases/elftest.html. Accessed October 7, 2019.

2. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. Oct 2002;97(10):2614-2618. PMID 12385448.

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

76981
76982
76983
81596
84999
91200
0002M
0003M