diagnosis and monitoring of liver fibrosis in patients ... · pdf filemeasure liver stiffness...

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TITLE: Diagnosis and Monitoring of Liver Fibrosis in Patients with Chronic Hepatitis C: A Review of the Clinical Evidence and Cost Effectiveness

DATE: 8 March 2012 CONTEXT AND POLICY ISSUES Chronic hepatitis C (CHC) represents an important public health problem.1-3 It was estimated that in 2007, 242,000 Canadians had CHC and about 7,000 new infections occurred, mostly due to injection drug abuse.4 Hepatic fibrosis caused by CHC may gradually cause cirrhosis, liver failure, and hepatocellular carcinoma (HCC).5 It was reported that, of those with chronic hepatitis C, 15% to 25% will develop progressive liver disease, end stage liver disease, hepatocellular carcinoma or will require liver transplant.6,7 Therefore, the diagnosis and monitoring of liver fibrosis is essential in the management of patients with chronic hepatitis C.8-13 Liver biopsy has traditionally been considered the gold standard for the evaluation of hepatic

fibrosis and is used as a benchmark for initiating treatment.8,10,14-16 Liver biopsy has been used

in clinical trials for the confirmation of chronic hepatitis and to rule out other causes such as alcohol or fatty liver, as well as to identify cirrhosis. In addition, liver biopsy can differentiate different types of liver diseases such as steatosis, steatohepatitis or iron overload, which provides useful information for patient management and prognosis.8,17 The Metavir score (F0-F4) is widely used for grading the severity of hepatic fibrosis.18 F0 indicates no scarring; F1 indicates minimal scarring; F2 indicates that scarring has extended to outside the areas in the liver that contain blood vessels; F3 indicates bridging fibrosis is spreading and connecting to other areas that contain fibrosis; and F4 indicates cirrhosis or advanced scarring of the liver.18 Recently, telaprevir and boceprevir, two members of a novel class of drugs to treat CHC viral infection called NS3 protease inhibitors, were approved in Canada. Grading of hepatic fibrosis through liver biopsy was required for enrolment in the pivotal trials of these agents.19-22 The Canadian Drug Expert Committee (CDEC) recommended that boceprevir and telaprevir be listed for the treatment of chronic hepatitis C genotype 1 infection in patients with compensated liver disease, one of the criteria being that patients have a fibrosis score of F2, F3, or F4.23,24 The listing criteria for these agents were reflective of the enrolment criteria in the pivotal trials of

Diagnosis and Monitoring of Liver Fibrosis in Patients with Hepatitis C 2

the protease inhibitors, in that liver biopsy was specified as the method for determining the degree of fibrosis. The limitations of liver biopsy include the fact that it is an invasive procedure, observer variability, sampling error and lack of suitability for longitudinal monitoring.17,25-27 More importantly, it is associated with rare but potentially life-threatening complications.17,25-27 It was reported that the rates of severe complications and mortality associated with liver biopsy were 3% and 0.03% respectively.28 Liver biopsy is also associated with significant costs and requires expertise of a specialist.29 These limitations of liver biopsy have led to the development of non-invasive methods.8 Currently available tests rely on two different but complementary approaches: a 'biological' approach based on serum biomarkers of fibrosis and a 'physical imaging' approach based on the measurement of liver stiffness using transient elastography.1,10 Serum markers of fibrogenesis include platelet counts, prothrombin time, gamma-glutamyl transpeptidase (GGT), hyaluronic acid (HA) type IV collagen, metalloproteinase, inhibitors of metalloproteinase and transforming growth factor beta (TGF-β), and the ratio of alanine aminotransferase (ALT) to aspartate aminotransferase (AST) levels.10,30 Several scoring systems including Fibrotest (FT), Forn’s index, AST-platelet ratio index (APRI), Hepascore (HS) and Fibrometer (FM) have been proposed with various detection thresholds.30,31 FT is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoprotein A1, haptoglobin, GGT and bilirubin).32 FIB-4 is a test using the following formula: age (in years) x AST [U/L]/(platelets [109 /L] x (ALT [U/L])1/2).33 The Sequential Algorithm for Fibrosis Evaluation (SAFE) and the Bordeaux Algorithm (BA), which cross-check FT with the APRI or TE, have also been reported to be accurate but provide only a binary diagnosis of significant fibrosis (equivalent to Metavir >F2) or cirrhosis (equivalent to F4).34 Transient elastography (TE) is a commonly used method employing ultrasound technology to measure liver stiffness using a device commercially known as Fibroscan (EchoSens).35 Estimates of liver stiffness by TE correlate with fibrosis stage.36 TE can be performed in approximately 95% of patients, although older patients and patients who are obese can be more difficult to study. This technique has been evaluated most consistently in patients with chronic HCV disease.37 In Canada, most academic centres have access to Fibroscans. Serum fibrosis markers are used in various locations particularly in rural centres that do not have access to Fibroscan, but are not used systematically and not always reimbursed. It was reported that the average costs for liver biopsy, FT and Fibroscan were $1255, $350 and $131 (US$) respectively.29 Compared with liver biopsy, non-invasive testing algorithms may result in short-term cost savings, but the consequences of misdiagnosis in terms of health outcomes and treatment costs may outweigh the short-term gains in cost and convenience.29 Hence, an assessment of the clinical performance and cost effectiveness of non-invasive tests against liver biopsy is required to inform policy in this area. The aim of this review is to evaluate the evidence regarding the validity of non-invasive methods and their cost effectiveness compared with liver biopsy in the diagnosis and monitoring of liver fibrosis in patients with chronic hepatitis C viral infection. This report was reviewed by a clinical expert in the treatment of hepatitis C.


RESEARCH QUESTIONS 1. What is the comparative accuracy and validity of non-invasive methods versus liver biopsy

for detecting and grading liver fibrosis in patients with chronic hepatitis C viral infection? 2. What is the cost effectiveness of non-invasive methods versus liver biopsy for detecting

and grading liver fibrosis in patients with chronic hepatitis C viral infection? KEY MESSAGE Various non-invasive methods including transient elastography, Fibrotest, and aminotransferase-to-platelet ratio index have been studied for the detection and grading of hepatic fibrosis in patients with chronic hepatitis C viral infection. Diagnostic accuracy (sensitivity, specificity, positive predictive value and negative predictive value) for all tests compared with liver biopsy varied across studies. Moderate to high area under receiver-operator curve (AUROC) values (range: approximately 0.7 to 1.0) were reported for the three tests (FT, TE, and APRI) that had the largest body of evidence to validate them. Accuracy was generally higher for cirrhosis compared with earlier stages of fibrosis. Despite its limitations, liver biopsy remains the gold standard in terms of accuracy of diagnosis. There is limited evidence on the cost-effectiveness of non-invasive methods, and further studies are required. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2011, Issue 4), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and abbreviated list of major international health technology agencies, as well as a focused Internet search. No methodological filters were applied to limit retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2007 and January 6, 2012.

An additional limited literature search was conducted on the EMBASE database using the OVID platform to identify emerging evidence. No methodological filters were applied to limit retrieval by study type, except to limit the search by conference abstracts. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2011 and January 23, 2012. Rapid Response reports are organized so that the evidence for each research question is presented separately. Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications, and evaluated the full-text publications for the final article selection, according to the selection criteria presented in Table 1.


Table 1: Selection Criteria

Population

Patients with chronic hepatitis C viral infection

Intervention

Non-invasive techniques for detecting and grading liver fibrosis

Comparator

Liver biopsy

Outcomes

Accuracy and validity of noninvasive tests to detect and grade liver fibrosis (such as Area Under Receiver Operator Characteristic Curve, sensitivity, specificity, etc.) Cost-effectiveness

Study Designs

Health technology assessments, systematic reviews and meta-analyses, randomized controlled trials (RCTs), non-randomized studies, economic evaluations

Exclusion Criteria Studies were excluded if they did not meet the selection criteria, included a mixed population (such as co-infection with hepatitis B) without a subgroup analysis for patients with hepatitis C, and duplicate publications. Critical Appraisal of Individual Studies QUADAS checklists,38,39 AMSTAR check list40 and Drummond’s check list41,42 were used to assess the methodological quality for the included non-randomized studies, systematic reviews and economic evaluations, respectively. SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 289 citations. Upon screening titles and abstracts, 221 citations were excluded, and 68 potentially relevant articles were retrieved for full-text review. Of these, 38 did not meet the inclusion criteria. Thirty studies were included in this review.14,30,32,35,43-68 The study selection process is outlined in Appendix 1. Among the 30 included studies, four65-68 were systematic reviews or meta-analyses assessing the comparative accuracy and validity of non-invasive methods for detecting the hepatic fibrosis in patients with chronic hepatitis C, and twenty five30,32,35,43-65 were observational studies. One study14 evaluating the cost effectiveness of FT versus liver biopsy for detecting and grading liver fibrosis in U.S. patients with chronic hepatitis C viral infection was identified. Summary of Study Characteristics What is the comparative accuracy and validity of non-invasive methods versus liver biopsy for detecting and grading liver fibrosis in patients with chronic hepatitis C infection? The main characteristics of the included studies evaluating the validity of non-invasive methods are summarized in Appendix 2.


Among the 29 included studies comparing test accuracy, four65-68 were systematic reviews that assessed one or more of FT , TE, and APRI. Twenty five 30,32,35,43-64 were observational studies, nineteen30,35,43-45,47-60 of which were prospective observational studies, four32,46,64,69 were retrospective observational cohort studies, and two61,63 were cross-sectional studies. All studies were conducted in adults and two 46,56 also included a pediatric population. Three43,67,68 studies were from Canada and three 35,44,46 from the United States. The remainder were from France,30,51,53,55,57,59,61,62,64,65 Romania,47,49,52 Italy,70,71 Germany,32,63 Taiwan,48 Argentina,56 Tunisia,45 Parkistan,50 Turkey58 and China.66

Study sample sizes ranged from 2546 to 1289.62,64 Eight trials published in nine articles32,43,46,48,57,61,62,64,65 were conducted in patients with hepatitis C who were co-infected with hepatitis B or had other liver diseases, but subgroup data for hepatitis C were provided. One prospective study30 and three systematic reviews66-68 were conducted in patients with hepatitis C co-infected with human immunodeficiency virus (HIV). Commonly reported non-invasive methods for detecting hepatic fibrosis in the included studies were Transient elastography (TE, or Fibroscan), Aspartate Aminotransferase to Platelet Ratio Index (APRI) and Fibrotest (FT). Other non-invasive methods such as Hepascore (HS), Forn’s score, MP3, TGF-β1, tissue inhibitor of matrix metalloprotein inhibitor-1 (TIMP-1), hyaluronic acid (HA) and aminoterminal peptide of procollagen type III (PIIINP), Acoustic Radiation Force Impulse Imaging (ARFI), FIB4, and AP index were also reported in the included studies. The main outcomes reported were area under receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The AUROC is an estimate of the probability of a true diagnosis. An AUROC of 1.0 (100%) indicates a test can classify a patient with perfect accuracy, while an AUROC of 0.5 indicates that a test has a 50% chance of correct classification. What is the cost effectiveness of non-invasive methods versus liver biopsy for detecting and grading liver fibrosis in patients with chronic hepatitis C infection? Liu et al14 assessed the cost-effectiveness in the United States of six diagnostic strategies involving FT and liver biopsy, used alone or sequentially, followed by treatment of patients with hepatitis C with a telaprevir-based triple therapy regimen. This review focuses on the results of two strategies, i.e., FT only or liver biopsy only. In the FT group, patients were treated if significant fibrosis (F2-F4) was detected; otherwise, FT was repeated at regular intervals. In the liver biopsy only group, patients showing significant fibrosis and without medical contraindication was treated, otherwise biopsy was repeated every 3 years. A Markov model of chronic HCV infection was developed for tracking fibrosis progression. Outcomes were expressed as expected lifetime costs (2009 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER). The study characteristics are briefly summarized in Table 2.


Table 2: Characteristics of Included Economic Evaluations First Author, Publication Year, Country

Study Design, Time horizon

Patient Characteristics

Intervention Comparators Assumptions

Liu,14

2011, USA

Cost utility analysis (Time horizon: not reported)

Patients with hepatitis C

(One of six diagnostic strategies.) FT only: If test score < 0.31 (mild fibrosis, F0–F1), FT repeated annually. If > 0.31 and < 0.58 (intermediate fibrosis), FT repeated every six months. If > 0.58 (significant fibrosis, F2–F4), then treatment initiated if no medical contraindication

(One of six diagnostic strategies.) Liver Biopsy only: Those with results showing significant fibrosis without medical contraindication were treated, otherwise re-biopsied every 3 years

●Modeled utility decrements from biopsy as a one-time disutility of -0.05 (equivalent to a loss of 18 days); from standard 1-year treatment as -0.11 (equivalent to a loss of 40 days) ●Assumed disutility of -0.165 for one year of triple therapy (equivalent to a loss of 60 days) ●Decrements were scaled by the actual time on treatment

Summary of Critical Appraisal The risk of bias and generalizability of all included studies in the report are summarized in Table 3 and Appendix 3. The methodological quality of included studies for TE, FT and APRI were briefly summarized below. Risk of bias for studies on transient elastography

One systematic review68 and thirteen observational studies32,43,47-49,52,54,57,59-62,64 assessed the validity of transient elastography. The risk of bias of the systematic review68 was rated as uncertain because the time interval between liver biopsy and TE was not reported at the level of individual studies. Among the 13 observational studies, the risk of bias of was rated as low in six studies,52,54,57,59-61 and high in four studies32,47,62,64 because patients were selected retrospectively or the time interval between TE and liver biopsy was long (≥6 months). The risk of bias of the remaining three studies43,48,49 was uncertain because the time interval between TE and liver biopsy was not clearly reported. Test procedures were described adequately in all studies, and there were no apparent issues with respect to generalizability.

Risk of bias for studies on FibroTest Two systematic reviews65,68 and nine observational studies32,45,51,53,55,58,59,62,64 assessed the validity of FT in the assessment of hepatic fibrosis compared with liver biopsy. One SR65 was rated as being at high risk of bias because the literature search was not comprehensive. The risk of bias for the second SR68 was rated as uncertain because the time interval between liver biopsy and FT was not reported at the study level. Among the nine observational studies assessing FT, four 53,55,58,59 were rated as low risk of bias, and three32,62,64 were rated as high


risk because patients were selected retrospectively or the time interval between FT and liver biopsy was long (≥6 months). The risk of bias for two studies45,51 was rated as uncertain because the time interval between FT and liver biopsy was not clearly reported. Test procedures were described adequately in all studies, and there were no apparent issues with respect to generalizability.

Risk of bias for studies on Aminotransferase to Platelet Ratio Index

Two systematic reviews66,67 and eight observational studies30,46,50,53,55,58-60, assessed the validity of APRI in the prediction of hepatic fibrosis compared with liver biopsy. The risk of bias of both SRs was rated as uncertain because the time interval between liver biopsy and APRI was not reported at the study level. All observational studies except one50 were rated as being at low risk of bias; the exception was rated as uncertain because the time interval between APRI and liver biopsy was not clearly reported. Test procedures were described adequately in all studies, and there were no apparent issues with respect to generalizability.

The risk of bias and generalizability of studies relating to other non-invasive tests are summarized in Appendix 3.

Table 3: Critical Appraisal of Included SRs with AMSTAR40

First Author, Publication

Year, Country

Non-invasive

tests investigated

Strengths Limitations

Halfon,65

2008, France

FT ●a priori research questions and selection criteria were reported ●Hand searching was reported ●Characteristics of included study was provided ●Conflict of interest was declared;

●List of excluded studies was not provided ●Only one database was searched ●Quality assessment of included studies was not provided; ●Duplicate process of election and data extraction were not reported ●Publication bias was not provided

Shaheen,68

2007, Canada

FT TE

●a priori research questions and selection criteria were reported ●more than two databases searched ●Characteristics of included studies were provided ●List of excluded and excluded studies was provided ●Selection and data extraction were duplicated ●Quality assessment of included studies was provided

●Publication bias was not provided ●Conflict of interest was not declared

Lin ,66

2011, China

APRI ●a priori research questions and selection criteria were reported ●more than two databases searched ●Characteristics of included study were provided ●Selection and data extraction were duplicated ●Quality assessment of included studies was provided

●List of excluded studies was not provided ●Publication bias was not assessed ●Conflict of interest was not declared

Shaheen,67

2007, Canada

APRI ●a priori research questions and selection criteria were reported ●more than two databases searched

●List of excluded studies was not provided ●Publication bias was not assessed



Year, Country

Non-invasive

tests investigated

Strengths Limitations

●Characteristics of included studies were provided ●Selection and data extraction were duplicated ●Quality assessment of included studies was provided

●Conflict of interest was not declared

The included economic evaluation was also considered to have significant methodological limitations because elements of the study design, such as source of data, sample size and time horizon were not clearly reported (Table 4). Table 4: Critical Appraisal of Included Economic Evaluations with Drummond’s check list41,42


Year, Country

Non-invasive tests

investigated Strengths Limitations

Liu,14

2011, USA

One of six diagnostic strategies involving FT

●Research questions and selection criteria were reported. ●Choice of model used and the key parameters on which it was based were justified.

●The model does not stratify the population by race. ●Sample size and time horizon were not specified. ●Sources of effectiveness estimates were not based on randomized studies. ● Strategy set is not comprehensive. ●Conflict of interests was not declared.

Summary of Findings What is the comparative accuracy and validity of non-invasive methods versus liver biopsy for detecting and grading liver fibrosis in patients with chronic hepatitis C? The main findings of the included studies are summarized below and in Appendix 4. Transient elastography

One systematic review68 and thirteen observational studies32,43,47-49,52,54,57,59-62,64 assessed the validity of TE in the assessment of hepatic fibrosis compared with liver biopsy. Based on the results of four studies included in their systematic review, Shaheen et al. reported that at cut-off values of between 0.31-8.74 kpa (i.e., patients with values above the cutoff are classified as having hepatic fibrosis scores of F2-F4), the AUROC, sensitivity, specificity, PPV, and NPV were 0.72 – 1.0, 55%-100%, 18% - 100%, 64% - 100% and 48%-100%, respectively.68 For cirrhosis, the AUROC was 0.95. The authors concluded that FT is useful for identification of cirrhosis, but less so for assessment of earlier stages of disease due to lower accuracy. Further refinement of the method was deemed necessary before FT could replace liver biopsy.68 The findings from the 13 observational studies revealed that at cut-off values between 5.2 -12.9 kPa, AUROCs ranged from 0.74 to 0.91 for Metavir score F2-F3, and 0.94 to 0.98 for F4 (cirrhosis). The sensitivity ranged from 60% to 90% for F2-F3 and 87% to 96% for F4; specificity was 32% to 93% for F2-F3 and 81% to 94% for F4. The positive predictive value ranged from


33% to 98% for F2-F3, and from 39% to 73% for F4. Negative predictive values were 30% to 79% for F2-F3 and 96% to 99% for F4. FibroTest

Two systematic reviews65,68 and nine observational studies32,45,51,53,55,58,59,62,64 assessed the validity of FT in the assessment of hepatic fibrosis compared with liver biopsy. In the systematic review by Halfon,65 the reported AUROC for detecting fibrosis stages of F2-F4 was 0.79 (cut-off value not reported) based on the results of 19 included studies. In the second systematic review, Shaheen68 reported based on nine included studies that at the cut off value of up to 0.6 for classifying patients as F2-F4, the ranges for AUROC, sensitivity, specificity, positive predictive value and negative predictive value were 0.78 – 0.84, 35% - 39% , 87%-92%, 16%-86% and 76% -94%, respectively. For cirrhosis, the AUROC was 0.90. Similar to their assessment of TE, Shaheen et al. concluded that FT was useful for identification of cirrhosis but less so for earlier stages of fibrosis. Further development was felt to be necessary before the method could replace liver biopsy.68 In contrast, Halfon concluded that FT was as accurate as liver biopsy and could be used as an alternative to biopsy. 65 In the nine observational studies32,45,51,53,55,58,59,62,64, at cut-off values ranging from 0.22 to 0.75 for fibrosis (F0-F4), the reported AUROCs ranged from 0.56 to 0.82. Sensitivity ranged from 45% to 92%, and specificity was 54% to 90%. The positive predictive value ranged from 16% to 89%; and the negative predictive value was 52% to 99%. Aminotransferase to Platelet Ratio Index

Two systematic reviews66,67 and eight observational studies30,46,50,53,55,58-60 assessed the validity of APRI in the prediction of hepatic fibrosis compared with liver biopsy. In one systematic review by Lin,66 which included 40 studies, overall ranges for AUROC, sensitivity, specificity, positive predictive value and negative predictive value at cut-offs ranging from 0.5 to 1 (for classifying patients as ≥F2 to F4), were 0.77 – 0.83, 74% - 76%, 49%-72%, 55 % and 69% respectively. The author’s assumed optimal cutoff values for significant fibrosis (>F2) and F4 were 0.7 and 1, respectively. The ranges for AUROC, sensitivity, specificity, positive predictive value and negative predictive value at the optimal cut-off value (i.e. 0.7) for fibrosis >F2 were 77%, 72%, 70% and 79%, respectively. The ranges for AUROC, sensitivity, specificity, positive predictive value and negative predictive value at the optimal cut-off value (i.e. 1.0 ) for F4 were 76%, 72%, 55% and 69%, respectively. The authors concluded that APRI demonstrated a moderate degree of accuracy compared with liver biopsy.66 In the second systematic review by Shaheen,67

at cut-off values ranging from 0.5 to 1 (for ≥F2 to F4), the reported AUROC, sensitivity, specificity, positive predictive value and negative predictive value were 0.76 – 0.82, 76 % - 81 %, 50% - 71%, 32% -59%, and 75% -94 % respectively. The authors concluded that the main advantage of APRI was its ability to exclude significant hepatic fibrosis.67

Data from eight observational studies30,46,50,53,55,58-60 showed that at cut-off values ranging from >0.5 to 2.0, the reported AUROCs ranged from 0.75 to 0.82 for fibrosis scores of F2-F3, and 0.56 to 0.82 for F4 (cirrhosis). The sensitivity ranged from 18% to 66% for F1-F3 and 0% to 33% for F4, while specificity was 50% to 91% for F1-F3 and 74% to 100% for F4. The positive predictive value ranged from 10% to 90% for F1-F3 and 0% to 100% for F4, and the negative predictive value ranged from 56% to 92% for F1-F3 and 90% to 92% for F4.


Hepascore

Four observational studies30,53,55,59 assessed the validity of Hepascore (HS) in the prediction of hepatic fibrosis compared with liver biopsy. At a cut-off values of 0.5 to 0.84 (for classifying patients as F0-F4), AUROC ranged from 0.79 to 0.90, sensitivity ranged from 33% to 86%, and specificity ranged from 73 to 92%. The positive predictive value ranged from 29% to 81% and the negative predictive value ranged from 63% to 99%.

Forn’s score

Three observational studies30,55,59 assessed the validity of Forn’s score in the prediction of hepatic fibrosis compared with liver biopsy. At a cut-off values of 4.2 to 4.9 (for classifying patients as F0-F4), the AUROCs for Forn’s score ranged from 0.77 to 0.78; sensitivity ranged from 45% to 94%, and specificity ranged from 41 to 90%. Positive predictive value ranged from 39% to 82% and the negative predictive value ranged from 62% to 95%.

Other tests

Limited evidence showed that MP3, 55,59 TGF-β1,56 TIMP-1,56 PIIINP56, FIB4,58,59 APFI,47,60 ELFT 32, ELFG 59 score and suPAR 63 were also predictive of liver fibrosis. Detailed results are summarized in Appendix 4.

What is the cost effectiveness of non-invasive methods versus liver biopsy for detecting and grading liver fibrosis in patients with chronic hepatitis C viral infection? In the cost-effectiveness analysis by Liu et al.14 the total costs associated with the FT alone strategy for men and women were 193,979 US $ and 213,525 US $ respectively. The total costs associated with the liver biopsy alone strategy for men and women were 195,169 US $ and 214,760 US $ respectively. The total QALYs from FT alone for men and women were 15.01 to 16.19 respectively. The QALYs from liver biopsy alone for men and women were 14.85 and 16.01 respectively. The ICERs showed that FT dominated liver biopsy (Table 5). The author concluded that in clinical settings where testing is required prior to treatment, FT alone is more effective and less costly than liver biopsy. These results were robust to multi-way and probabilistic sensitivity analyses. Table 5: Cost-Effectiveness Results reported by Liu et al.14 by Gender and Genotype Genotype 1 Tests Cost (US$) QALY ICER ($/QALY)

Men FT Only 193,979 15.01 –

Liver Biopsy Only 195,169 14.85 dominated

Women FT Only 213,525 16.19 –


Genotype 2&3 Tests Cost (US$) QALY ICER ($/QALY)

Men FT Only 188,070 16.51 dominated


Women FT Only 208,296 17.64 dominated


ICER=incremental cost-effectiveness ratios. Dominated=strategy costs more but achieves less QALYs than the previous strategy or a combination of strategies


Emerging Evidence Nine conference abstracts were identified regarding the validity of non-invasive methods versus liver biopsy for detecting and grading liver fibrosis in patients with chronic hepatitis C (CHC) and are summarized in Appendix 5. The non-invasive markers, indices, and tests used to detect and grade liver fibrosis in these studies were: FibroTest72; hyaluronic acid72; FIB-4 index73,74; King’s score73; MAR-C index 75; aspartate transaminase (AST)76; alanine transaminase (ALT)76; aspartate amino transferase to platelet ratio index (APRI)76-78; ultrasonography to determine portal vein cross sectional area76; acoustic radiation force impulse (ARFI)77; methacetin breath test (MBT)77; FibroMax77; transient elastography (TE)78; laminin-based score (LBS)79; and the enhanced liver fibrosis test (ELFT)80. Limitations The methodological quality of one of the included systematic reviews was rated as poor65 because the literature search was not comprehensive, a duplicate process for study selection or data extraction was not described and quality assessment results for included studies were not reported. The quality of the remaining systematic reviews66-68 was rated as uncertain because the time interval between liver biopsy and the non-invasive methods was not reported at the level of the individual study. The risk of bias of six observational studies43,45,48-51,62,64 was rated as uncertain because the time interval between the index test and liver biopsy was not clearly reported. Five studies32,46,47,62,64 were rated as having a high risk of bias because the patients were selected retrospectively and/or the time interval between index test and liver biopsy was too long (≥6 months). In addition, the cut off value for each non-invasive method was not consistently applied in all included studies, which may limit the ability to make direct comparisons of diagnostic validity across the included studies. Other differences across studies, such as in the standardization of test procedures and training of investigators may also impact the ability to compare results. Although liver biopsy remains the gold standard for detecting and grading liver fibrosis, it also has important shortcomings due to sampling error, inter-rater variability, and the lack of a universally accepted scoring system. Differences in the performance of liver biopsy may therefore result in variability in the measured diagnostic accuracy of non-invasive tests across studies. Only a small number of studies (6 of 30) were conducted in North America. Analyses conducted in countries other than Canada may not be transferable to the Canadian setting due to practice variations and differences in availability of specific tests. One study reported a cost-effectiveness analysis for FT along strategy compared with liver biopsy along strategy, although there were a number of methodological limitations limiting the quality of the analysis. No evidence of cost effectiveness was available for other non-invasive tests. None of the studies identified assessed the effect of non-invasive tests on clinical endpoints such as progression of fibrosis, risk of hepatic complications, or death. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Liver biopsy is currently the gold standard for identifying and grading liver fibrosis in patients infected with hepatitis C virus. This is reflected in the pivotal trials of the latest class of therapies approved for CHC viral infection, the protease inhibitors, which specified liver biopsy as a


criterion for enrolment. Nevertheless, this invasive method is associated with a small risk of serious complications, and its accuracy may be compromised by factors such as sampling variability and inter-rater variability. Hence, there is interest in the potential for non-invasive tests to be used as an alternative to biopsy. In the included studies, diagnostic accuracy was mostly assessed at the level of disease stage categories, e.g., significant fibrosis (F2-F4) versus less severe fibrosis (<F2), rather than at the level of specific Metavir scores, although several studies differentiated cirrhosis (F4) from less advanced disease. The available evidence showed that the diagnostic validity of non-invasive methods for detecting liver fibrosis varied widely with the different cut-off values applied. Moderate to high AUROC values (range: approximately 0.7 to 1.0) were reported for the three tests (FT, TE, and APRI) for which there was the largest body of evidence. Systematic reviews of TE and FT concluded that these methods were most accurate for patients with cirrhosis, and less so for earlier stages of fibrosis. FT was deemed to be of sufficient accuracy to replace liver biopsy in one systematic review, but not in another despite similar AUROC values in both reviews. APRI was shown to demonstrate moderate diagnostic accuracy by systematic reviews that have assessed this method. Compared with TE, FT, and APRI, there was generally less evidence available for other tests. Although one analysis from the U.S. showed that FT may be more cost effective than liver biopsy, the findings must be interpreted with caution because of the methodological limitations of the study and issues of generalizability to the Canadian setting. More studies of the comparative cost effectiveness of non-invasive tests versus liver biopsy are needed in the Canadian setting. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


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Appendix 1: Selection of Included Studies

221 citations excluded

46 potentially relevant articles retrieved for scrutiny (full text, if

available)

22 potentially relevant reports retrieved from other sources (grey

literature, hand search)

68 potentially relevant reports

38 reports excluded: -irrelevant population (11) -irrelevant intervention (4) -irrelevant outcomes (9) -other (review articles, editorials) (12) -Duplicate publication (2)

30 reports included in review

267 citations identified from electronic literature search and

screened


Appendix 2: Characteristics of Included Studies on Clinical Effectiveness and Safety First Author, Publication Year, Country

Study Design, Length of Study

Patient Characteristics, Sample Size

Intervention Comparators Main Outcomes

Systematic review/meta-analysis

Lin,66

2011, China

Meta-analysis

Adult patients with hepatitis C virus mono-infection or co-infected with HIV # of included studies=40 # of included patients: 8739 Data not pooled

APRI LB Metavir score Sensitivity, Specificity,

Halfon,65

2008, France

SR Adult patients with hepatitis C 19 studies, # of patients: NR (subgroup data for CHC)

FT LB AUROC

Shaheen,67

2007, Canada

SR Adult patients with hepatitis C virus mono-infection or co-infected with HIV # of included studies=22 # of included patients: 4266

APRI LB Metavir score Sensitivity, Specificity, PPV NPV

Shaheen,68

2007, Canada

SR Adult patients with hepatitis C virus mono-infection or co-infected with HIV # of included studies 9 for FT; 4 for TE; # of included patients: 1679 for FT; 546 for TE;

FT TE

LB Metavir score Sensitivity, Specificity, PPV NPV

Observational studies

Zarski,59

2012, France

Non-randomized study, prospective 2 years

Adult patients with hepatitis C N=382

Fibrometer FT Forn’s score APRI MP3 score ELFG score HS FIB4 HA TE

LB Metavir score AUROC Sensitivity, Specificity, PPV NPV

Usluer,58

2012, Turkey

Non-randomized study, prospective


AP index APRI FIB4 FT

LB Metavir score Sensitivity, Specificity, PPV


First Author, Publication Year, Country




6 months

NPV

Valva,56

2011, Argentina

Non-randomized study, prospective Duration: NR

Adult and Pediatric patients with hepatitis C N=44 (adult, 22 and children 22)

TGF-β1 TIMP-1 HA PIIINP


Rizzo,60

2011, Italy

Non-randomized study, prospective 1 year


TE ARFI


Cardoso,61

2011, France

Non-randomized study, cross-sectional

Adult patients with hepatitis C N=363 (subgroup for HCV)

TE LB Metavir score AUROC Sensitivity, Specificity, PPV NPV

Poynard,62,64

2011, France

Non-randomized study, retrospective 1 year

Adult patients with hepatitis C N=1289 (subgroup for HCV)

TE FT ALT

LB Metavir score AUROC, Sensitivity Specificity

Berres,63

2011, Germany

Non-randomized study, cross-sectional


suPAR LB Metavir score AUROC

Myers,43

2010 Canada

Non-randomized study, prospective 6 months

Adult patients with hepatitis C N=133 (53%)

TE

LB Metavir score AUROC Sensitivity, Specificity, PPV NPV Accuracy of TE

Said,45

2010, Tunisia

Non-randomized study, prospective 2 years


FT LB Metavir score AUROC Sensitivity, Specificity, PPV NPV

McGoogan, 46

2010 USA

Non-randomized study: retrospective data analysis, 16 years

Pediatric patients with hepatitis C (Age 1-20 years average age: 11.6) N=25 (69%)

APRI LB Metavir score AUROC Sensitivity, Specificity, PPV NPV

Degos,57

2010, France

Non-randomized study, prospective,

Adult patients with hepatitis C N=913 (67%, 913/1307,

TE (FibroScan)

LB Metavir score AUROC Sensitivity, Specificity,






2 years subgroup analysis)

PPV NPV

Malik,44

2010, USA

Non-randomized study, prospective, 3 years

Adult patients with hepatitis C N=238 (238/404, 59%. Subgroup data for HVC was provided)

TE HA APRI AST/ALT ratio


Friedrich-Rust,

32

2010, Germany

Non-randomized study, retrospective 3 years

Adult patients with hepatitis C N=36 (subgroup data for CHC)

TE FT ELFT

LB Metavir score Sensitivity, Specificity, PPV NPV

Lupsor,47

2009, Romania

Non-randomized study, prospective, 2 months


ARFI TE


Wang,48

2009, Taiwan


Adult patients with hepatitis C N=214 (214/320, 67%, Subgroup data for HVC was provided)


Kirk,35

2009, USA

Non-randomized study, Prospective and some data from database) Length of study: 15 months

Adult patients with hepatitis C co-infected with HIV; N=192

TE LB Metavir score Sensitivity, Specificity, PPV NPV

Sporea,49

2008 Romania

Non-randomized study, Prospective, 12 months


TE


Fontanges,5

1

2008, France

Non-randomized Study, prospective, 6 months


FT LB Metavir score AUROC Sensitivity, Specificity, PPV NPV

Lupsor,52

2008 Romania

Non-randomized Study, prospective, 10 months



Bourliere,53

2008, France

Non-randomized study,


FT APRI HS

LB Metavir score AUROC Sensitivity,






prospective, ≤I year

Specificity, PPV NPV

Arena,54

2008, Italy

Non-randomized study, prospective, 10 months



Khan,50

2008, Pakistan



APRI LB Metavir score AUROC Sensitivity, Specificity, PPV NPV

Cacoub,30

2008, France

Non-randomized study, prospective, Length of study: not reported

Adult patients with hepatitis C co-infected with HIV N=272

Fibrometer(FM) FT Forns’ score APRI HS FIB4 SHASTA

LB Metavir score AUROC

Leroy,55

2007, France



MP3 ( PIIINP plus MMP-1) FT, Fibrometer, Hepascore, Forns' score APRI


AP index= Age+platelet count (range,0–10) (Age (years): <30=0; 30–39=1; 40–4902; 50–59=3; 60–69=4; ≥70=5; Platelet count (x 109/l): ≥225=0; 200–224=1; 175–199=2; 150–174=3; 125–149=4; <125=5); APRI= aspartate aminotransferase to platelet ratio index; ARFI= Acoustic Radiation Force Impulse Imaging; AST= Aspartate transaminase; ALT= Alanine transaminase; ELFG= European Liver Fibrosis Group; AUROC=Area under receiver operating characteristic Curve; ELFT= Enhanced Liver Fibrosis test consisting of an algorithm of three fibrosis markers (HA, PIIINP andTIMP-1). FT=Fibrotest consisting of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoprotein A1, haptoglobin, GGT and bilirubin); GGT=Gamma-glutamyl transferase; HA= hyaluronic acid; HS= Hepascore; LB= liver biopsy; Metavir score= Metavir fibrosis score F0 – F4: F0=no fibrosis, F2=significant fibrosis, F3=severe fibrosis and F4=cirrhosis; MMP-1=Matrix metalloproteinase I; MP3=combination of PIIINP and MMP-1; NPV=negative predictive value; PIIINP=aminoterminal peptide of procollagen type III; PPV=positive predictive value; suPAR=soluble urokinase plasminogen activator receptor, HIV= human immunodeficiency virus ; FM= Fibrometer=[-0.07 platelets(10

9 /l)-0.049 PI(%)+0.012 AST(UI/l)+0.005 A2M(mg/dl)+0.021 HA(ug/l)-0.27 year (mmpl/l)+0.027 age+3.718]; SHASTA=[-

3.84+1.7 (1 if HA 41-85ng/ml, 0 other wise)+3.28 (1 if HA >85 ng/ml, 0 otherwise) +1.58 (albumin <3.5 g/dl, 0 otherwise) + 1.78 (if AST >60 IU/l, 0 otherwise)] ≤F1 if SHASTA <0.3 and ≥F2 if SHASTA>0.8. ; TE= Transient elastography (also called: ultrasound elastography or Fibroscan); TIMP-1= tissue inhibitor of matrix metalloprotein inhibitor-1.


Appendix 3: Critical Appraisal of Included Studies with QUADAS Checklists38,39 First Author, Year, Country

Index test studied

Risk of bias Applicability concerns Patient Selection

Index test

Reference test

Flow and time

Patient Selection

Index test

Reference test


Lin ,66

2011, China

APRI L L L ? L L L

Halfon,65

2008 France

FT H L L H L L L

Shaheen,67

2007, Canada

APRI L L ? ? L L L

Shaheen,68

2007, Canada

FT TE L L ? ? L L L


Zarski,59

2012, France

Fibrometer FT Forn’s score APRI MP3 score ELFG score HS FIB4 HA TE

L L L L L L L

Usluer,58

2012, Turkey

AP index APRI FIB4 FT

L L L L L L L

Valva,56

2011, Argentina

TGF-β1 TIMP-1 HA PIIINP

L L L L L L L

Rizzo,60

2011, Italy

TE ARFI L L L L L L L

Cardoso,61

2011, France

TE L L L L L L L

Poynard,62,64

2011, France

TE FT ALT

H L L ? ? L L

Berres,63

2011, Germany

suPAR L L L L L L L

Myers,43

2010 Canada

Transient elastography (TE)

L L L ? L L L

Said,45

2010 Tunisia

FT L L L ? L L L

McGoogan,46

APRI H L L ? H L L


First Author, Year, Country

Index test studied

Risk of bias Applicability concerns 2010 USA

Degos,57

2010, France

TE (FibroScan) L L L L L L L

Malik,44

2010, USA

TE HA APRI AST/ALT ratio

L L L L L L L

Friedrich-Rust,

32

2010, Germany

TE FT ELFT

L L L H L L L

Lupsor,47

2009, Romania

ARFI TE L L L H L L L

Wang,48

2009, Taiwan

TE L L L ? L L L

Kirk,35

2009, USA

TE ? L L ? L L L

Sporea,49

2008 Romania

TE L L L ? L L L

Fontanges,51

2008, France

FT L L L ? L L L

Lupsor,52

2008 Romania

TE L L L L L L L

Bourliere,53

2008, France

FT APRI HS

L L L L L L L

Arena,54

2008, Italy

TE L L L L L L L

Khan,50

2008, Pakistan

APRI L L L ? L L L

Cacoub,30

2008, France

Fibrometer(FM) FT Forns’ score APRI HS FIB4 SHASTA

L L L L L L L

Leroy,55

2007, France

MP3 ( PIIINP plus MMP-1) FT Fibrometer, Hepascor Forns' Score APRI

L L L L L L L

L=low risk; H=high risk; ?=unclear;


Appendix 4: Main Study Findings and Authors’ Conclusions First Author, Publication Year, Country

Main results Author’s Conclusions


Lin, 66

2011, China

APRI: For ≥F2 (significant fibrosis) (n=6259 from 33 studies) AUROC: 0.77 for combined different stage of fibrosis at cut-off of 0.5 Sensitivity: 74% Specificity: 49% PPV:55% NPV:69% At cut-off of 0.7 (optimal) Sensitivity: 77% Specificity: 72% PPV:70% NPV:79% at cut-off of 1.5 Sensitivity: 37% Specificity: 93% PPV:82% NPV:63% For ≥F3 (severe fibrosis) (n=4441 from 13 studies) AUROC: 0.80 for combined different stage of fibrosis At cut-off of 1 (optimal) Sensitivity: 61% Specificity: 64% PPV:40% NPV:81% For F4 (cirrhosis) (n=4548 from 18 studies) AUROC: 0.83 for combined different stage of fibrosis At cut-off of 1 (optimal) Sensitivity: 76% Specificity: 72% PPV:55% NPV:69% At cut-off of 2 Sensitivity: 46% Specificity: 91% PPV:82% NPV:63%

On page 726: “Our large meta-analysis suggests that APRI can identify hepatitis C-related fibrosis with a moderate degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among chronic hepatitis C patients.”

Halfon,65

2008, France

FT

AUROC: (cut off: not reported) 0.79 (for F2-F4) On page 22: “Fibrotest is an effective alternative to liver biopsy in patients with hepatitis C. Indeed, the prognostic performance value of FT was at least as accurate as that of biopsy.”

Shaheen,67

2007,

APRI For ≥ F2 (F2 – F4) AUROC: 0.76

On page 912:”The major strength of the APRI is the exclusion of significant HCV-related fibrosis.




Canada At cut-off of 0.5 Sensitivity: 81% Specificity: 50% PPV:59% NPV:75% At cut-off of 0.7 Sensitivity: 84% Specificity: 70% PPV:NR NPV:NR At cut-off of 1.0 Sensitivity: 59% Specificity: 86% PPV:NR NPV:NR At cut-off of 1.5 Sensitivity: 35% Specificity: 91% PPV:77% NPV:61% For cirrhosis: AUROC: 0.82 At cut-off of 1.0 Sensitivity: 76% Specificity: 71% PPV:32% NPV:94% At cut-off of 2.0 Sensitivity: 49% Specificity: 91% PPV:50% NPV:91%

Future studies of novel markers should demonstrate improved accuracy and cost-effectiveness compared with this economical and widely available index.”

Shaheen,68

2007, Canada

FT

For ≥F2 (F2-F4) at cut-off of ≤ 0.6 AUROC: 0.78 – 0.84 Sensitivity: 35% - 39% Specificity: 87%-92% PPV:16-86% NPV:76-94% For cirrhosis: AUROC: 0.90 TE

On page 2589: “FibroTest and FibroScan have excellent utility for the identification of HCV-related cirrhosis, but lesser accuracy for earlier stages. Refinements are necessary before these tests can replace liver biopsy”




For ≥F2 (F2-F4) cut off value: 0.31 – 8.74 kpa AUROC: 0.72 – 1.0 Sensitivity: 55%-100% Specificity: 18% - 100%PPV:64% - 100% NPV:48%-100% For cirrhosis: AUROC: 0.95


Zarski,59

2012, France

(≥F2 and F4 respectively) Fibrometer: Cut-off: 0.411 and 0.88 for ≥F2 and F4

respectively AUROCs: 0.83 and 0.90 Sensitivity: 87 % and 70% Specificity: 56% and 89% PPV: 64% and 51% NPV: 84% and 94% FT: Cut-off 0.48 and 0.74 for ≥F2 and F4 respectively

AUROCs: 081 and 0.87 Sensitivity: 76 % and 71% Specificity: 66% and 81% PPV: 66% and 39% NPV: 76% and 94% Forn’s score AUROC : 0.77 for ≥F2 APRI: Cut-off 0.5 and 2.0 for ≥F2 and F4 respectively

AUROCs: 0.78 and 0.87 Sensitivity: 33 % and 7.1% Specificity: 97% and 98% PPV: 89% and 80% NPV: 62% and 86% MP3 score:

AUROC:0.76 for ≥F2 ELFG score:

AUROC:0.78 and 0.87 for ≥F2 and F4 respectively HS: Cut-off 0.5 and 0.84 for ≥F2 and F4 respectively

AUROCs: 0.82 and 0.89 for ≥F2 and F4 respectively Sensitivity: 75 % and 77% Specificity: 73% and 81% PPV: 70% and 41% NPV: 77% and 95% FIB4:

AUROC:0.78 and 0.84 for ≥F2 and F4 respectively HA:

AUROC:0.74 for ≥F2 TE: cut-off 5.2 and 12.9 for for ≥F2 and F4 respectively

AUROCs: 0.82 and 0.84 for ≥F2 and F4 respectively

On page 55: “Contrarily to blood tests, performance of Fibroscan was reduced due to uninterpretable results. Fibrotest , interpretable Fibroscan, Fibrometer, and Hepascore perform best and similarly for diagnosis of significant fibrosis and cirrhosis.”




Sensitivity: 97 % and 77% Specificity: 35% and 87% PPV: 56% and 57% NPV: 92% and 96%

Usluer,58

2012, Turkey

For F3-F4 FT: cut off: 0.31

Sensitivity: 89% Specificity: 64% PPV: 46% NPV: 95% FIB4: cut off: 1.45

Sensitivity: 62% Specificity: 67% PPV: 37% NPV: 85% APRI: cut off: 0.5

Sensitivity: 71% Specificity: 55% PPV: 34% NPV: 85% AP index: cut off: 3.9

Sensitivity: 69% Specificity: 49% PPV: 30% NPV: 83%

On page 5: “In conclusion, mild to moderate fibrosis cases are difficult to recognize, even with the most successful noninvasive serum markers. Our study suggests that fibrosis tests may better serve to exclude significant fibrosis rather than detect fibrosis; especially FibroTest, FIB4, APRI, or AP index may be used to exclude significant fibrosis with a NPV >80%. A liver biopsy still has a major role in the proper diagnosis of liver fibrosis in patients infected with HCV who cannot be excluded using non-invasive tests.”

Valva,56

2011, Argentina

In Children: TGF-β1(pg/ml) at cut-off: 6.95 and 8.8 for ≥F2 and ≥F3

respectively AUROCs: 0.55 and 0.57 for for ≥F2 and ≥F3 respectively Sensitivity: 88% and 60% for ≥F2 and ≥F3 respectively Specificity: 44% and 70% for ≥F2 and ≥F3 respectively PPV: 74% and 33% for ≥F2 and ≥F3 respectively NPV: 68% and 86% for ≥F2 and ≥F3 respectively TIMP-1 (ng/ml) at cut off: 105 and 166 for ≥F2 and ≥F3

respectively AUROCs: 0.63 and 0.8 for ≥F2 and ≥F3 respectively Sensitivity: 81% and 80% for ≥F2 and ≥F3 respectively Specificity: 56% and 70% for ≥F2 and ≥F3 respectively PPV: 76.5% and 40% for ≥F2 and ≥F3 respectively NPV: 63% and 93% for ≥F2 and ≥F3 respectively HA (ng/ml) at cut-off: 24 and 43 for ≥F2 and ≥F3

respectively AUROCs: 0.59 and 0.56 for ≥F2 and ≥F3 respectively Sensitivity: 40% and 25% for ≥F2 and ≥F3 respectively Specificity: 89% and 100% for ≥F2 and ≥F3 respectively PPV: 86% and 100% for ≥F2 and ≥F3 respectively NPV: 47% and 87% for ≥F2 and ≥F3 respectively PIIINP (µg/L) at cut-off: 10 and 9.6 for ≥F2 and ≥F3

respectively AUROCs: 0.65 and 0.7 for ≥F2 and ≥F3 respectively Sensitivity: 47% and 75% for ≥F2 and ≥F3 respectively Specificity: 100% and 83% for ≥F2 and ≥F3 respectively PPV: 100% and 50% for ≥F2 and ≥F3 respectively NPV: 47% and 94% for ≥F2 and ≥F3 respectively

On page 2: “In adults given the diagnostic accuracy of HA, PIIINP, TGF-β1, their combination may provide a potential useful tool to assess liver fibrosis. This first pediatric study suggests that TIMP-1 is clinically useful for predicting liver fibrosis in HCV patients.”




In adults: TGF-β1(pg/ml) at cut-off: 11 and 11 for ≥F2 and ≥F3

respectively AUROCs: 0.79 and 0.84 for for ≥F2 and ≥F3 respectively Sensitivity: 75% and 100% for ≥F2 and ≥F3 respectively Specificity: 80% and 65% for ≥F2 and ≥F3 respectively PPV: 82% and 46% for ≥F2 and ≥F3 respectively NPV: 73% and 100% for ≥F2 and ≥F3 respectively TIMP-1 (ng/ml) at cut off: 336 and 655 for ≥F2 and ≥F3

respectively AUROCs: 0.56 and 0.55 for for ≥F2 and ≥F3 respectively Sensitivity: 42% and 20% for ≥F2 and ≥F3 respectively Specificity: 80% and 100% for ≥F2 and ≥F3 respectively PPV: 71% and 100% for ≥F2 and ≥F3 respectively NPV: 53% and 81% for ≥F2 and ≥F3 respectively HA (ng/ml) at cut-off: 103 and 109 for ≥F2 and ≥F3

respectively AUROCs: 0.78 and 0.93 for for ≥F2 and ≥F3 respectively Sensitivity: 67% and 100% for ≥F2 and ≥F3 respectively Specificity: 90% and 82% for ≥F2 and ≥F3 respectively PPV: 89% and 63% for ≥F2 and ≥F3 respectively NPV: 62% and 100% for ≥F2 and ≥F3 respectively PIIINP (µg/L) at cut-off: 9 and 9 for ≥F2 and ≥F3 respectively

AUROCs: 0.79 and 0.89 for for ≥F2 and ≥F3 respectively Sensitivity: 75% and 100% for ≥F2 and ≥F3 respectively Specificity: 80% and 65% for ≥F2 and ≥F3 respectively PPV: 82% and 46% for ≥F2 and ≥F3 respectively NPV: 73% and 100% for ≥F2 and ≥F3 respectively

Rizzo,60

2011, Italy

TE : (kPa) cut-off 6.5 , 8.8 and 11 for ≥F2 , ≥F3 and F4

respectively AUROCs: 0.78, 0.83 and 0.80 for ≥F2, ≥F3 and F4 respectively Sensitivity: 71 %, 77% and 70% Specificity: 71%, 85% and 82% PPV: 82%, 77% and 53% NPV: 56% , 85% and 90% APRI: (m/s)Cut-off:1.3 1.7 and 2.0 for ≥F2 and F4

respectively AUROCs: 0.86, 0.94 and 0.89 Sensitivity: 81% , 91% and 83 % Specificity: 70%, 86% and 86% PPV: 81%, 80% and 63% NPV: 68%, 94 and 95%

On page 2112: “In a cohort of patients with CHC, ARFI imaging was more accurate than TE for the non-invasive staging of both significant and severe classes of liver fibrosis.”

Cardoso,61

2011, France

TE : (kPa) cut-off : about 7.1, 9.5 and 12.5 for ≥F2 , ≥F3 and

F4 respectively AUROCs: 0.78, 0.86 and 0.93 for ≥F2, ≥F3 and F4 respectively Sensitivity: 68 %, 68% and 84% Specificity: 89%, 92% and 94% PPV: 88%, 73% and 58% NPV: 70% , 90% and 98%

On page 1: “TE measurement accurately predicts the absence or presence of significant fibrosis, advanced fibrosis or cirrhosis In hepatitis C patients.”




Poynard,62,64

2011, France

FT : (for ≥F2 and F4 respectively)

AUROCs: 0.75 and 0.85 Sensitivity: 66% and 68% Specificity: 85% and 89% TE: (for ≥F2 and F4 respectively)

AUROCs: 0.76 and 0.90 Sensitivity: 48% and 65% Specificity: 93% and 95% ALT: (for ≥F2 and F4 respectively)

AUROCs: 0.62 and 0.62 Sensitivity: 73% and 42% Specificity: 70% and 83%

On page 720: “A method without the use of a gold standard confirmed the accuracy of FibroTest and Fibroscan for the diagnosis of advanced fibrosis and cirrhosis in patients with chronic hepatitis C. The variability of the model was mostly due to the discordances between Fibroscan and biopsy”

Berres,63

2011, Germany

suPAR:

For F1/F2 vs. F3/F4 AUROCs: 0.77 For F1/F2/F3 vs. F4: AUROCs: 0.79

On page 1: “Serum suPAR levels were robust markers of liver fibrosis in 2 cohorts with a comparable diagnostic accuracy for prediction of severe liver fibrosis as established noninvasive marker.”

Myers,43

2010 Canada

TE:

AUROCs(95%CI) of TE for Metavir fibrosis scores of F2 and F3 or greater, and F4 were 0.74 (95% CI 0.68 to 0.80), 0.89 (95% CI 0.84 to 0.94), and 0.94 (95% CI 0.90 to 0.97), respectively At a cut off of 11.1 kPa: For cirrhosis (prevalence 53%) Sensitivity: 96% Specificity: 81% PPV: 39% NPV: 99% At a cut off of 7.7 kPa: For ≥ F2 (prevalence 53%) Sensitivity: 68% Specificity: 69% PPV: 70% NPV: 65%

On page 661: “The major role of TE is the exclusion of bridging fibrosis and cirrhosis. However, TE cannot replace biopsy for the diagnosis of significant fibrosis”.

Said,45

2010, Tunisia

FT:

(F0-F1 vs. F2-F4) at a cut-off of 0.5) AUROCs: 0.87, P<0.0001 Sensitivity: 85% Specificity: 72% PPV: 89% NPV: 65% (F0-F2 vs. F3-F4) at a cut-off of 0.52) AUROCs(95%CI): 0.76, (P<0.0001) Sensitivity: 92% Specificity: 54% PPV: 57% NPV: 91% (F0-F3 vs. F4) at a cut-off of 0.75) AUROCs(95%CI): 0.85, (P<0.002) Sensitivity: 86%

On page 573: “This prospective study confirmed the good diagnostic value of Fibrotest as compared with the liver biopsy”




Specificity: 71% PPV: 26% NPV: 97%

McGoogan,46

2010 USA

APRI: [for fibrosis (F0-F3) and cirrhosis (F4)]

AUROCs (95%CI) of TE for Metavir fibrosis score (95%CI): for fibrosis: 0.75 (0.52 to0.97); For cirrhosis: 0.56 (0.00 to 1.00); At APRI >0.5 For Fibrosis Sensitivity: 47% Specificity: 90% PPV: 80% NPV: 65% For Cirrhosis: Sensitivity: 33% Specificity: 73% PPV: 10% NPV: 92% At APRI > 1.5 For Fibrosis: Sensitivity: 18% Specificity: 100% PPV: 100% NPV: 58% For cirrhosis Sensitivity: 0% Specificity: 91% PPV: 0% NPV: 91%

On page 344: “The APRI performed better in older patients and in those with vertically transmitted hepatitis C virus. Further research into APRI in children with chronic viral hepatitis is needed”

Degos,57

2010, France

Subgroup data for patients with hepatitis C TE(Fibroscan): at cut-off: 5.2 for ≥F2

AUROCs: 0.75 Sensitivity: 90% Specificity: 32% PPV: 68% NPV: 66% No subgroup data for hepatitis C were provided for FT, Fibrometer, or APRI

On page 1013: “The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.”




Malik,44

2010, USA

TE LS (kPa) cut-off: 12 for cirrhosis(F4)

AUROCs: 0.9 Sensitivity: 92% Specificity: 88% PPV: 87% NPV: 90% HA cut-off: >150ng/mL for cirrhosis(F4)

AUROCs: 0.81 Sensitivity: 74% Specificity: 79% PPV: 77% NPV: 69% APRI cut-off: >1 for cirrhosis(F4)

AUROCs: 0.71 Sensitivity: 73% Specificity: 54% PPV: 52% NPV: 71% AST/ALT ratio (cut-off: >1 for cirrhosis(F4)

AUROCs: 0.66 Sensitivity: 64% Specificity: 59% PPV: 58% NPV: 60%

On page 1562: “Transient elastography accurately identified compensated cirrhosis; a liver stiffness of >12 kPa represents an important clinical measurement for the diagnosis of cirrhosis”

Friedrich-Rust,

32

2010, Germany

FT : cut-off 0.32 , 0.59 and 0.73 for ≥F2 , ≥F3 and F4

respectively Sensitivity: 81 %, 65% and 67% Specificity: 60%, 79% and 81% PPV: 84%, 73% and 54% NPV: 55% , 71% and 88% ELF : cut-off 9.8, 10.2 and 10.3 for ≥F2 , ≥F3 and F4

respectively Sensitivity: 85 %, 82% and 89% Specificity: 80%, 74% and 63% PPV: 92%, 74% and 44% NPV: 67% , 82% and 94% TE (kPa): cut-off 7.2, 12.5 and 12.5 for ≥F2 , ≥F3 and F4

respectively Sensitivity: 79%, 67% and 78% Specificity: 50%, 79% and 84% PPV: 79%, 71% and 64% NPV: 50% , 75% and 91%

On page 1: “FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography”

Lupsor,47

2009, Romania

ARFI

SWV cut-off for ≥F1, ≥F2, ≥F3 and F4 were >1.19, , >1.34, >1.61 and >2.00 respectively. AUROCs: 0.73, 0.87, 0.9, 0.94 for ≥F1, ≥F2, ≥F3 and F4 respectively. Sensitivity: 62%, 68%, 79% and 80% for ≥F1, ≥F2, ≥F3 and F4 respectively Specificity: 86%, 93%, 95% and 95% for ≥F1, ≥F2, ≥F3 and

On page 303: “ARFI allows SWV quantification, in strong correlation with the fibrosis stage. The maximal performance of the method consists of the prediction in severe fibrosis and cirrhosis. The diagnostic accuracy is strongly comparable to TE only for the prediction of severe




F4 respectively PPV: 96%, 93%, 92% and 90% for ≥F1, ≥F2, ≥F3 and F4 respectively NPV: 27%, 67%, 86% and 90% for ≥F1, ≥F2, ≥F3 and F4 respectively TE

LS(kpa) cut-off for ≥F1, ≥F2, ≥F3 and F4 were >5.2 , >8.1, >9.6 and >13.1 respectively. AUROCs: 0.92, 0.96, 0.96, 0.97 for ≥F1, ≥F2, ≥F3 and F4 respectively. Sensitivity: 85%, 85%, 96% and 80% for ≥F1, ≥F2, ≥F3 and F4 respectively Specificity: 93%, 95%, 87% and 89% for ≥F1, ≥F2, ≥F3 and F4 respectively PPV: 99%, 97%, 85% and 85% for ≥F1, ≥F2, ≥F3 and F4 respectively NPV: 48%, 80%, 96% and 97% for ≥F1, ≥F2, ≥F3 and F4 respectively

fibrosis and cirrhosis, whereas for earlier stages, TE performs better.”

Wang, 48

2009, Taiwan

TE

LS (kPa) cut-off: 6.5, 9.5 and 12 for ≥F1, ≥F2 and F4 respectively.

AUROCs: 0.86, 0.82, 0.87, 0.93 for ≥F1, ≥F2, ≥F3 and F4 respectively. Sensitivity: 75%, 69% an 89% for ≥F1, ≥F2 and F4 respectively (no data for ≥F3) Specificity: 78%, 81%, 84% for ≥F1, ≥F2 and F4 respectively (no data for ≥F3) PPV: 95%, 72%, 53% for ≥F1, ≥F2 and F4 respectively (no data for ≥F3) NPV: 35%, 78%, 97% for ≥F1, ≥F2 and F4 respectively (no data for ≥F3)

On page 439: “LSM is useful for predicting hepatic fibrosis and excluding cirrhosis. “

Kirk,35

2009, USA

TE

For ≥F2 cutoff: ≥9.3kPa AUROC: 0.81 Sensitivity: 86% Specificity: 75% PPV: 67% NPV:90% For cirrhosis: cutoff: ≥12.3kPa

AUROC: 0.81 Sensitivity: 75% Specificity: 86.1% PPV: 64% NPV:91%

On page 964: “For most HCV-infected persons, fibrosis stage predicted by elastography is similar to that predicted by examination of a biopsy specimen. Elastography-based measurement of liver stiffness holds promise to expand liver disease screening and monitoring, particularly among injection drug users”

Sporea,49

2008 Romania

TE:

AUROCs of TE for Metavir fibrosis scores of F2 or greater: 0.773 At a cut off of 6.8 kPa: Sensitivity: 59.6%

On page 6513: “In patients with chronic hepatitis due to HCV, a cut-off value of 6.8 kPa measured by TE can differentiate between significant fibrosis and absent or mild fibrosis




Specificity: 93.3% PPV: 98% NPV: 30.1%

with a PPV of 98%, a NPV of 30.1%, a sensitivity of 59.6%, a specificity of 93.3%, and a diagnostic performance of 77.3%”

Fontanges,51

2008, France

FT:

(F0-F1 vs. F2-F4) at a cut-off of 0.385) AUROCs(95%CI) :0.73(0.63 to 0.83), (P<0.0001) Sensitivity: 74% Specificity: 61% PPV: 45% NPV: 82% (F0-F2 vs. F3-F4) at a cut-off of 0.455) AUROCs(95%CI): 0.81(0.71 to 0.90), (P<0.0001) Sensitivity: 86% Specificity: 68% PPV: 52% NPV: 92%

On page 859: “This study confirms the good diagnostic value of biochemical tests for hepatic fibrosis as compared with liver biopsy. However, clinicians must interpret Actitest and Fibrotest results with caution in patients with a significant elevation of ALT, and/or GGT and/or alpha2-macroglobulin which could overestimate hepatic injury.”

Lupsor,52

2008 Romania

TE:

( The cut-off value for ≥F1, ≥F2, ≥F3 and F4 were 4.9 kPa, 7.4 kPa, 9.1 kPa and 11.85 kPa respectively) AUROCs for ≥F1, ≥F2, ≥F3 and F4 were 0.936, 0.862, 0.910 and 0.938 respectively Sensitivity: for ≥F1, ≥F2, ≥F3 and F4 were 87.54%, 75.96%, 87.79% and 86.96% respectively. Specificity: for ≥F1, ≥F2, ≥F3 and F4 were 92.3%, 83.64%, 83.96% and 90.76% respectively. PPV: for ≥F1, ≥F2, ≥F3 and F4 were 99.63%, 89.77%, 73.02% and 72.29% respectively NPV: for ≥F1, ≥F2, ≥F3 were 24%, 64.79%, 92.71% and 96.17% respectively.

On page 155: “Transient elastography is a useful method for chronic hepatitis C assessment. Fibrosis is the main predictor of liver stiffness, but activity and steatosis, also influence liver stiffness”

Bourliere,53

2008, France

FT:

AUROCs for ≥F2, ≥F3 and F4 were 0.83, 0.84 and 0.89 respectively Sensitivity: for ≥F2, ≥F3, and F4 were 62%, 69% and 91% respectively. Specificity: for ≥F2, ≥F3, and F4 were 86%, 86% and 75% respectively PPV: for ≥F2, ≥F3, and F4 were 82%, 65% and 23% respectively NPV: for ≥F2, ≥F3, and F4 were 69%, 88% and 99% respectively Overall accuracy: for ≥F2, ≥F3, and F4 were 74%, 80% and 75% respectively HS:

AUROCs for ≥F2, ≥F3, and F4 were 0.82, 0.84 and 0.90 respectively, Sensitivity: for ≥F2, ≥F3, and F4 were 58%, 69% and 86% respectively. Specificity: for ≥F2, ≥F3, and F4 were 86%, 87% and 83% respectively PPV: for ≥F2, ≥F3, and F4 were 81%, 67% and 29% respectively NPV: for ≥F2, ≥F3, and F4 were 67%, 88% and 99%

On page 458: “Hepascore is an accurate non-invasive marker for ≥F2 and F4 diagnosis in HCV patients. In a pragmatic approach, a stepwise optimized algorithm combining APRI and FT or HS considerably increases diagnostic accuracy and avoided liver biopsies”




respectively Overall accuracy: for ≥F2, ≥F3, and F4 were 72%, 82% and 83% respectively APRI:

AUROCs for ≥F2: 0.76 Forn’s score:

AUROCs for ≥F2: 0.73

Arena,54

2008, Italy

TE:

AUROCs for ≥F2, ≥F3 and F4 were 0.91, 0.99 and 0.98 respectively Cut-off value for ≥F2, ≥F3 and F4 were 7.8, 10.8 and 14.8 kpa respectively. Sensitivity: for ≥F2, ≥F3, and F4 were 83%, 91% and 94% respectively. Specificity: for ≥F2, ≥F3, and F4 were 82%, 94% and 92% respectively PPV: for ≥F2, ≥F3, and F4 were 83%, 89% and 73% respectively NPV: for ≥F2, ≥F3, and F4 were 79%, 95% and 98% respectively.

On page 1288: “TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis”

Khan,50

2008, Pakistan

APRI (for F0 to F4)

AUROCs: 0.82 (mean value at cut off: 0.5 and 1.5) Sensitivity: 66% and 41% at cut off of 0.5 and 1.5 respectively Specificity: 83% and 90% at cut off of 0.5 and 1.5 respectively PPV: 72% and 58% at cut off of 0.5 and 1.5 respectively NPV: 78% and 90% at cut off of 0.5 and 1.5 respectively

On page 122: “APRI could correctly identify significant fibrosis in 48% and advanced fibrosis in 66% cases with acceptable degree of diagnostic accuracy in CHC patients in our clinical practice.”

Cacoub,30

2008, France

AUROC: (cut off: not reported) For ≥F2 For FM, HS, FT, Fib-4 SHASTA, APRI and Forn’s score were 0.70, 0.69, 0.64, 0.65, 0.64, 0.65 and 0.59 respectively For ≥F3 For FT, HS, FM, Fib-4 SHASTA, APRI and Forn’s score were 0.78, 0.76, 0.72, 0.69, 0.68, 0.67 and 0.66 respectively For ≥F4 For FT, HS, FM, Fib-4 SHASTA, APRI and Forn’s score were 0.84, 0.83, 0.81, 0.72, 0.72, 0.70 and 0.79 respectively

On page 765: “In HIV/HCV co-infected patients, Fibrometer, Hepascore and Fibrotest outperformed other non-invasive liver fibrosis biomarkers for the prediction of significant liver fibrosis.”




Leroy,55

2007, France

FT:

AUROCs for F0-F1 vs. F2-F4: 0.84; for F0-F2 vs. F3-F4: 0.87 At cut-off value 0f >0.22 to 0.59 Sensitivity: 89.0 – 45.1% and 94.7 – 66.7% for F2-F4, and F3-F4, respectively. Specificity: 52.8-89.9% and 41.9 – 87.6% for F2-F4, and F3-F4, respectively PPV: 65.9-82.0% and 39 – 68% for F2-F4, and F3-F4, respectively NPV: 82.5-61.5% and 94.7-86.9% for F2-F4, and F3-F4, respectively. APRI:

AUROCs for F0-F1 vs. F2-F4: 0.81; for F0-F2 vs. F3-F4: 0.82 At cut-off value 0f >0.5 to 2.0 Sensitivity: 91.6 – 57.8% and 93.5 – 73.9% for F2-F4, and F3-F4, respectively. Specificity: 26.8-93.9% and 21.8 – 84% for F2-F4, and F3-F4, respectively PPV: 55.9-90.6% and 31.6 – 64.2% for F2-F4, and F3-F4, respectively NPV: 75.9-68.8% and 89.7-91.6% for F2-F4, and F3-F4, respectively. Hepascore:

AUROCs for F0-F1 vs. F2-F4: 0.79; for F0-F2 vs. F3-F4: 0.85 At cut-off value 0f >0.5 to 0.84 Sensitivity: 53.8 – 33% and 76.5– 47.1% for F2-F4, and F3-F4, respectively. Specificity: 83.9-92% and 81.1 – 89.8% for F2-F4, and F3-F4, respectively PPV: 77.8-81.1% and 61.9 – 64.9% for F2-F4, and F3-F4, respectively NPV: 63.5-56.7% and 89.6-80.9% for F2-F4, and F3-F4, respectively. Forn’s score:

AUROCs for F0-F1 vs. F2-F4: 0.78; for F0-F2 vs. F3-F4: 0.78; At cut-off value 0f >4.2 to 6.9 Sensitivity: 88.4– 41.9% and 91.7– 54.2% for F2-F4, and F3-F4, respectively. Specificity: 42.4-92.9% and 34.1 – 87% for F2-F4, and F3-F4, respectively PPV: 60.8-85.7% and 35.2 – 61.9% for F2-F4, and F3-F4, respectively NPV: 78.3-61.2% and 91.3-82.9% for F2-F4, and F3-F4, respectively. MP3:

AUROCs for F0-F1 vs. F2-F4: 0.84;

On page 775: “Current non-invasive scores give reliable information on liver fibrosis in one-third of chronic hepatitis C patients, especially when used in combination.”




for F0-F2 vs. F3-F4: 0.88; At cut-off value 0f >0.2 to 0.5 Sensitivity: 95.6– 18.7% and 100– 31.4% for F2-F4, and F3-F4, respectively. Specificity: 23.9-98.9% and 19.5 – 98.4% for F2-F4, and F3-F4, respectively PPV: 56.5-94.4% and 33.1 – 88.9% for F2-F4, and F3-F4, respectively NPV: 84-54% and 100-78.3% for F2-F4, and F3-F4, respectively. Fibrometer:

AUROCs for F0-F1 vs. F2-F4: 0.86; for F0-F2 vs. F3-F4: 0.91; Sensitivity: NR Specificity: NR PPV: NR NPV: NR

AP index= Age+platelet count (range,0–10) (Age (years): <30=0; 30–39=1; 40–4902; 50–59=3; 60–69=4; ≥70=5; Platelet count (x 109/l): ≥225=0; 200–224=1; 175–199=2; 150–174=3; 125–149=4; <125=5); APRI= aspartate aminotransferase to platelet ratio index; ARFI= Acoustic Radiation Force Impulse Imaging; AST= Aspartate transaminase; ALT= Alanine transaminase; ELFG= European Liver Fibrosis Group; AUROC=Area under receiver operating characteristic curve; ELFT= Enhanced Liver Fibrosis test consisting of an algorithm of three fibrosis markers (HA, PIIINP andTIMP-1). FT=Fibrotest consisting of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoprotein A1, haptoglobin, GGT and bilirubin); GGT=Gamma-glutamyl transferase; HA= hyaluronic acid; HS= Hepascore; LB= liver biopsy; Metavir score= Metavir fibrosis score F0 – F4: F0=no fibrosis, F2=significant fibrosis, F3=severe fibrosis and F4=cirrhosis; MMP-1=Matrix metalloproteinase I; MP3=combination of PIIINP and MMP-1; NPV=negative predictive value; PIIINP=aminoterminal peptide of procollagen type III; PPV=positive predictive value; suPAR=soluble urokinase plasminogen activator receptor, HIV= human immunodeficiency virus ; FM= Fibrometer=[-0.07 platelets(10

9 /l)-0.049 PI(%)+0.012 AST(UI/l)+0.005 A2M(mg/dl)+0.021 HA(ug/l)-0.27 year (mmpl/l)+0.027 age+3.718]; SHASTA=[-

3.84+1.7 (1 if HA 41-85ng/ml, 0 other wise)+3.28 (1 if HA >85 ng/ml, 0 otherwise) +1.58 (albumin <3.5 g/dl, 0 otherwise) + 1.78 (if AST >60 IU/l, 0 otherwise)] ≤F1 if SHASTA <0.3 and ≥F2 if SHASTA>0.8; TE= Transient elastography (also called: ultrasound elastography or Fibroscan); TIMP-1= tissue inhibitor of matrix metalloprotein inhibitor-1


Appendix 5: Emerging Evidence from Conference Abstracts

Author, Year Study type, Country


Intervention and Comparators

Main Outcomes

Atef 2011, NRS

72

Egypt

Adult patients with chronic hepatitis C virus N=52

FT HA LB

F0-F1 (no or minimal fibrosis) vs. F2-F4 (significant fibrosis) FT at a cut-off of 0.19 AUROC: 0.6736 Sensitivity: 84.2% Specificity: 85.7% HA at a cut-off of71 mg/dL AUROC: 0.540 Sensitivity: 89.5% Specificity: 85.7% FT at cut-off 0.22 and HA at cut-off 71 mg/dL AUROC: 0.895 Sensitivity: 89.5% Specificity: 100%

Atta 2011, NRS

73

Egypt

Patients with chronic hepatitis C virus N=142

FIB-4 King’s score LB

F2-F3 (significant fibrosis) vs. F4 (cirrhosis) FIB-4 at a cut-off of 0.98 AUROC: 0.59 Sensitivity: 80% Specificity: 41% PPV: 94% NPV: 65.2% King’s score at a cut-off of 8.2 AUROC: 0.57 Sensitivity: 80% Specificity: 40% PPV: 86.4% NPV: 60%

Carrion 2011, NRS

75

Spain


MAR-C LB

MAR-C:

Cut-off <-1.50 for F0-F1 Sensitivity: 91% NPV: 91% Cut-off >1.38 for F2-F4 AUROC: 0.83 Specificity: 98% PPV: 90%

El-Attar 2011, NRS

76

Egypt


AST ALT APRI Ultrasonography LB

ALT <0.38 or HA<9.7 ng/ml or portal vein cross sectional area <25.8 mm

2 excludes significant

fibroses (≥F2) AST+ALT<39.5 or APRI<0.235 excludes presence of advanced fibrosis NPV: 100% APRI>1.1 to diagnose advanced fibrosis PPV: 100%

Fierbinteanu 2011, NRS

77

Romania


ARFI MBT FM

F≥2 (significant fibrosis) ARFI AUROC: 0.978 MBT





Main Outcomes

APRI LB

AUROC: 0.885 FM AUROC: 0.872 APRI AUROC: 0.763 F≥3 (advanced fibrosis) ARFI AUROC: 0.987 MBT AUROC: 0.922 FM AUROC: 0.901 APRI AUROC: 0.878

Gara 2011, NRS

78

North America

Patients with chronic hepatitis C virus with advanced fibrosis and cirrhosis N=134

TE APRI LB

Ishak 3-6 (advanced fibrosis) TE at cut-off of 8.9kPa Sensitivity: 90% Specificity: 78% PPV: 62% NPV: 95% APRI at cut-off of 0.8 Sensitivity: 81% Specificity: 76% PPV: 57% NPV: 91% Ishak 5-6 (cirrhosis) TE at cut-off of 13.1kPa Sensitivity: 100% Specificity: 89% PPV: 58% NPV: 100% APRI at cut-off of 1.0 Sensitivity: 79% Specificity: 78% PPV: 34% NPV: 96%

Salman 2011, NRS

79

Egypt


LBS LB

LBS:

Cut-off 0.545 to detect significant fibrosis (F3-F6, Knodell score) AUROC: 0.929 Sensitivity: 86% Specificity: 87% Cut-off 1.24 to detect cirrhosis AUROC: 0.985 Sensitivity: 100% Specificity: 98.7%





Main Outcomes

Shaikh 2011, NRS

74

Pakistan

Adult patients with chronic hepatitis C virus and severe fibrosis or cirrhosis N=115

FIB-4 LB

FIB-4:

Cut-off <1.45 for F≤2 (to exclude extensive fibrosis and cirrhosis) Sensitivity: 82.1% Specificity: 68.8% NPV: 78.6% Cut-off >3.25 for F3-F4 (to predict significant fibrosis and cirrhosis) Sensitivity: 22.9% Specificity: 100% PPV: 100%

Tanwar 2011, NRS

80

Multicentre

Adult patients with chronic hepatitis C virus previous non-responsive to pegylated interferon and ribavirin undergoing 24-month treatment with pegylated interferon and silymarin N=70

ELFT LB

ELFT:

F0-1 vs. F2-6 Pre-treatment AUROC: 0.832 Post-treatment AUROC: 0.830 F0-2 vs. F3-6 Pre-treatment AUROC: 0.847 Post-treatment AUROC: 0.802 F0-3 vs. F4-6 Pre-treatment AUROC: 0.811 Post-treatment AUROC: 0.858 F0-4 vs. F5-6 Pre-treatment AUROC: 0.868 Post-treatment AUROC: 0.891

ALT= alanine transaminase; AFRI=acoustic radiation force impulse; APRI= aspartate aminotransferase to platelet ratio index; AST= aspartate transaminase; AUROC=area under receiver operating characteristic curve; CBC=complete blood count; ELFT= Enhanced Liver Fibrosis test consisting of an algorithm of three fibrosis markers (HA, PIIINP andTIMP-1); F0-F4=Metavir fibrosis score; FIB-4=fibrosis index calculated by ASTxALT; FM=FibroMax consisting of five tests in one (FibroTest – liver fibrosis, ActiTest – active liver disease, SteatoTest – hepatitic steatosis, NashTest – non-alcoholic steatohepatitis); FT=FibroTest consisting of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoprotein A1, haptoglobin, GGT and bilirubin); GGT=Gamma-glutamyl transferase; HA= hyaluronic acid; King’s score=agexASTxinternational normalized ratio/platelets; LB= liver biopsy; LBS=laminin-based score=[13.0331 x S. laminin (mug/ml)] - [0.5681 x S. albumin (g/dl)] + [0.2001 x PV diameter (mm)] + [0.0079 x AST (IU/l)] - 3.8876; MAR-C=fibrosis index incorporating age, platelets, AST, GGT, prothrombin time; MBT=methacetin breath test; NPV=negative predictive value; NRS=non-randomized study; PIIINP=aminoterminal peptide of procollagen type III; PPV=positive predictive value; TE= transient elastography (also called: ultrasound elastography or Fibroscan); TIMP-1= tissue inhibitor of matrix metalloprotein inhibitor-1

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