PICO 4 Staging Effectiveness of non-invasive fibrosis testing in CHC

PICO 4 Staging

Effectiveness of non-invasive fibrosis testing in CHC

Emmanuel Tsochatzis Sheila Sherlock Liver Centre

Royal Free Hospital and UCL Institute of Liver and Digestive Health

Global Hepatitis Programme

Guideline development for Hepatitis C virus Screening, Care and Treatment in low- and middle-income countries

WHO/HIV/2014.30

© World Health Organization 2014

© World Health Organization 2014

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HTA Project: 09/114/02 - Cost-effectiveness of non- invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver

disease

• Royal Free & UCL

M Rodriguez, K Mantzoukis, E Thalassinos, J O’Brien, V Papastergiou K Gurusamy, B Davidson, AK Burroughs

• Brunel University

C Crossan, Louise Longworth

• Cochrane for advice on literature search (A Noel-Storr) & analysis

Disclosures

HTA Funding/Publication Acknowledgement:

This project was funded by the NIHR Health Technology Assessment programme (project number 09/114/02) and will be published in full in Health Technology Assessment journal. See the HTA programme website for further project information.

Department of Health Disclaimer:

The views and opinions expressed therein are those of the authors

and do not necessarily reflect those of the Department of Health.

Diagnostic accuracy tests

Paired diagnostic measures at specific thresholds Sensitivity = TP/(TP+FN)

Specificity = TN/(TN+FP)

Reference standard test

Disease positive Disease Negative

Test positive True positive (TP) False positive (FP)

Test negative False negative (FN) True negative (TN)

Consequences of True Positive (TP), False Positive (FP), False Negative (FN) and True Negative (TN)

• TP: higher priority treatment allocation preventive cirrhosis care and may reduce morbidity and mortality. TPs will have further testing which may increase anxiety, complications and resource use

• FP will likely have further testing and will increase anxiety, complications and resources use

• TN will likely be reassured, but may still be retested every year to detect new cases that develop

• FN will likely progress to hepatic decompensation and will experience increased mortality due to delayed diagnosis

• Strategy: ?Re-testing ?Treatment threshold ?Further testing

Diagnostic accuracy tests

Single diagnostic measure across different test thresholds

ROC AUC

K/F0 K/F1 K/F2 K/F3 K/F4

Indication for Treatment

Screening for HCC Screening for Oesophageal Varices

F: METAVIR S: ISHAK’s K: KLEINER

S0 S1 S2 S3-S4 S5-S6

End-Points of Histological Scoring Systems

Sub-classification of cirrhosis

D’Amico 2006, Arvaniti 2010, Fede 2012 One-year mortality 1-57%

<4% annual mortality >20% annual mortality

Non-invasive fibrosis markers

• Indirect serum tests

• Direct serum tests

• Imaging modalities

Procollagen III N peptide, Type IV collagen, Hyaluronic acid, YKL-40,

Collagenases & inhibitors: MMPs, TIMPs

Direct Markers

Matrix Components &

Enzymes regulating Fibrogenesis & Fibrolysis

Indirect Markers

Markers of Liver Inflammation & Liver

Function

AST, ALT, TP, platelets, γGT, bilirubin, Albumin,

cholesterol, ApoA1, α2 macroglobulin, haptoglobin

Combination of Direct & Indirect tests

Established and Candidate

Biomarkers of Liver Fibrosis

Non invasive markers of fibrosis and liver biopsy

Serum markers are calibrated with direct reference to liver biopsy, therefore replicate both correct and incorrect classification

Only Transient Elastography from currently available tests is independent of liver biopsy

Tsochatzis Hepatology 2011

Quality criteria for liver biopsy and Non-Invasive Tests (NITs)

• Biopsy of adequate length & number of portal tracts

• Serum tests – hemolysis, Gilbert, laboratory

• Imaging modalities – operator, manufacturer recommendations

Serum non-invasive tests

Test Components Cost

APRI

£3/free

FIB4

£3/free Forns

£3/free Fibrotest

apolipopotein, a2-macroglobulin

£43

Elastography

 This technology allows liver stiffness measurements which are:

 Repeatable and reproducible

 Independent of device and operator

Independent of organ movements (breathing, heartbeat,…)

 10 valid measurements with a success rate of >60% are

required

Factors that influence liver stiffness

Cholestasis

Amyloidosis

Meal

Congestion

(heart failure, …) Portal pressure

Acute inflammation, flares, elevated transaminases…

Other histological parameters

(inflammation, ballooning, steatosis…)

Fibrosis

(portal, sinusoidal, content…)

Methods of systematic review

• Search strategy defined

– MEDLINE, EMBASE, Science Citation Index

• At least two researchers

– Screened the abstracts

– Assessed quality of studies (QUADAS-2)

– Extracted data

Data extraction

• Index tests = various

• Target condition = various stages of fibrosis

• Reference standard = liver biopsy

• Max interval between LBx and index test 6 months

• True positive, false positive, false negative, true negative

• Bivariate model

– Currently considered one of the best models

– Summary sensitivity and specificity calculated at each threshold

– Metadas macro for SAS

Summary sensitivity and specificity of non-invasive tests to detect liver fibrosis stage Metavir >= F2

Test Studies, n

Patients Se 95% CI Sp 95% CI

APRI_low 47 11696 82 77-86 57 49-65

APRI_high 36 9602 39 32-47 92 89-94

Fibroscan 37 8346 79 74-84 83 77-88

Fibrotest 17 5083 68 57-77 72 67-77

FIB4_low 11 2744 89 79-95 42 25-61

FIB4_high 9 2115 59 43-73 74 56-87

Forns_low 18 4747 88 83-91 40 33-48

Forns_high 15 4132 35 29-41 96 92-98

PLT 10 2849 50 41-59 89 83-93

AST_ALT ratio 7 1665 44 27-63 71 62-78

Indirect Non-Invasive Test comparison for F2

Test 1 Test 2 P Driving force

APRI_low FIB4_low NS APRI_low FT

(Fibrotest)

FT specificity

APRI_low TE

(Transient elastography)

TE specificity

APRI_high FIB4_hig h

APRI se, sp

APRI_high FT APRI Se, sp

APRI_high TE TE Se, sp

Transient Elastography vs. APRI high cut-off for F2

Test Important Outcome

Results per 1000 patients tested (95% CI) Pre-test probability

20% Pre-test probability 80%

Elasto-

graphy APRI Elasto-

graphy APRI

True Positive (TP) 158

(148-168) 78

(64-94) 632

(592-672) 312 (256-376) TP absolute

difference⁽²⁾ 80 more

(74-84 more) 320 more (296-336 more)

False Positive (FP) 136

(96-184) 64

(48-88) 34

(24-46) 16

(12-22) FP absolute

difference⁽²⁾

72 more (48-96 more)

18 more (12-24 more)

False Negative

(FN) 42

(32-52) 122

(106-136) 168

(128-208) 488 (424-544) FN absolute

difference⁽²⁾ 80 fewer

(54-104 fewer) 320 fewer (296-336 fewer)

True Negative (FN)

664 (616-704)

736 (712-752)

166 (154-176)

184 (178-188) TN absolute

difference⁽²⁾ 72 fewer

(48-96 fewer) 18 fewer (12-24 fewer)

Transient Elastography vs. APRI low cut-off for F2

Test Important Outcome

Results per 1000 patients tested (95% CI) Pre-test probability

20% Pre-test probability 80%

Elasto-

graphy

APRI Elasto-

graphy

APRI True Positive (TP) 158

(148-168) 164

(154-172) 632

(592-672) 656 (616-688) TP absolute

difference⁽²⁾ 6 fewer

(4-6 fewer) 24 fewer (16-24 fewer)

False Positive (FP) 136

(96-184) 344

(280-408) 34

(24-46) 86

(70-102) FP absolute

difference⁽²⁾ 208 fewer

(184-224 fewer) 52 fewer (46-56 fewer)

False Negative (FN)

42 (32-52)

36 (28-46)

168 (128-208)

144 (112-184) FN absolute

difference⁽²⁾ 6 more

(4-6 more) 24 more (16-24 more)

True Negative

(FN) 664

(616-704) 456

(392-520) 166

(154-176) 114 (98-130) TN absolute

difference⁽²⁾ 208 more

(184-224 more) 52 more (46-56 more)

Summary of sensitivity and specificity for F4

Test Studies, n Patients Se 95% CI Sp 95% CI

APRI_low

24 7301 0.77 0.73-0.81 0.78 0.74-0.81 APRI_high

19 6930 0.48 0.41-0.56 0.94 0.91-0.95 Fibroscan

36 7923 0.89 0.84-0.92 0.91 0.89-0.93 Fibrotest

8 3724 0.60 0.43-0.76 0.86 0.81-0.91

PLT 13 2861 0.49 0.39-0.59 0.87 0.75-0.94

AST_ALT ratio

10 1984 0.68 0.59-0.76 0.86 0.72-0.94

Indirect Non-Invasive Test comparison for F4

Test 1 Test 2 P Driving force

APRI_low FT APRI_low Se, sp

APRI_low TE TE both

APRI_high FT APRI_high Se, sp

APRI_high TE TE Se

Transient Elastography vs. APRI low cut-off for F4

Test Important Outcome

Results per 1000 patients tested (95% CI) Pre-test probability

5% Pre-test probability 40%

Elasto-

graphy

APRI Elasto-

graphy

APRI True Positive (TP) 45

(42-46) 39

(37-41) 356

(336-368) 308 (292-324) TP absolute

difference⁽²⁾ 6 more

(1-9 more) 48 more (12-76 more)

False Positive (FP) 86 (67-105)

209 (181-247)

54 (42-66)

132 (114-156) FP absolute

difference⁽²⁾ 123 fewer

(114-142 fewer) 78 fewer (72-90 fewer)

False Negative (FN)

6 (4-8)

12 (10-14)

44 (32-64)

92 (76-108) FN absolute

difference⁽²⁾ 6 fewer

(2-10 fewer) 48 fewer (12-76 fewer)

True Negative

(FN) 865

(846-884) 741

(703-770) 546

(534-558) 468 (444-486) TN absolute

difference⁽²⁾ 124 more

(114-143 more) 78 more (72-90 more)

Transient Elastography vs. APRI high cut-off for F4

Test Important Outcome

Results per 1000 patients tested (95% CI) Pre-test probability

5% Pre-test probability 40%

Elasto-

graphy APRI Elasto-

graphy APRI

True Positive (TP) 45

(42-46) 24

(21-28) 356

(336-368) 192 (164-224) TP absolute

difference⁽²⁾ 21 more

(14-25 more) 164 more (144-172 more)

False Positive (FP) 86

(67-105) 57

(47-86) 54

(42-66) 36

(30-54) FP absolute

difference⁽²⁾

29 more (19-58 more)

18 more (12-36 more)

False Negative

(FN) 6

(4-8) 26

(22-30) 44

(32-64) 208

(176-236) FN absolute

difference⁽²⁾ 20 fewer

(18-22 fewer) 164 fewer (144-172 fewer)

True Negative (FN)

865 (846-884)

893 (865-903)

546 (534-558)

564 (546-570) TN absolute

difference⁽²⁾ 28 fewer

(21-57 fewer) 18 fewer (12-36 fewer)

Quality of evidence

Low: ++OO

Rated down for:

- Indirect comparisons (elastography vs. APRI);

- Risk of bias in elastography studies (including lack of validation of stiffness cut-offs);

- Disease prevalence might affect accuracy at specific cut-offs

- Reference test not always optimal (adequate liver

biopsy specimen; >/= 1.5 cm and >/= 6 portal tracts)

Important considerations

• Certified laboratory for Fibrotest components - ?applicability

• No validated Fibroscan cut-off for specific fibrosis stages

• Summary se, sp of Fibroscan most likely lower than reported

• Clinical practice: high and low values of Fibroscan

• Fibroscan not applicable in 10-20% of patients (body habitus)