To Pool or Not to Pool: To Pool or Not to Pool: POC Testing for

Hepatitis B and C

Sushmita ShivkumarMSc candidate, McGill University

Department of Epidemiology and Biostatistics

Sushmita.shivkumar@mail.mcgill.ca

1

We have no conflicts of interest with industry.

2

Background: Hepatitis BBackground: Hepatitis B

• 350 million worldwide with chronic Hepatitis B 350 million worldwide with chronic Hepatitis B (WHO).

• 4 million acute cases every year (WHO).y y ( )

3http://www.cdc.gov/ncphi/disss/nndss/casedef/hepatitiscacutecurrent.htm

Systematic ReviewSystematic Review• Objective:

To synthesize evidence on the diagnostic accuracy (sensitivity and specificity) of all POC tests used globally to diagnose Hepatitis B.

To critique the quality of studies that have been conducted to date using the QUADAS and STARD checklists for studies of diagnostic accuracyaccuracy.

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Search strategySearch strategy• Time period:

1985 20101985-2010

• Databases searched: Pubmed/Medline, Embase, Biosis, Web of Science.

• Search string :g("Hepatitis B"[Mesh] OR "Hepatitis B Antibodies"[Mesh] OR "Hepatitis B Surface Antigens"[Mesh] OR "Hepatitis B Core Antigens"[Mesh] OR "Hepatitis B Antigens"[Mesh] OR "Hepatitis B e Antigens"[Mesh]) AND ("Point-of-Care Hepatitis B e Antigens [Mesh]) AND ( Point-of-Care Systems"[Mesh] OR "rapid test*" OR "diagnostic") AND ("Sensitivity and Specificity"[Mesh] OR "diagnostic accuracy" OR "validity")

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Systematic review-SearchSystematic review SearchRecords identified through database searching 

tion

(n = 183)

gIden

tificat

Records after duplicates removed (n = 145)

EXCLUDED:  90Not looking at Hepatitis B = 46Other outcomes reported = 36

Screen

ing Other outcomes reported = 36

Not relevant = 8

Full‐text articles excluded (n =38)Not POC tests = 23Reviews = 4

Eligibility

Full‐text articles assessed for eligibility (n = 55)

Reviews = 4Not diagnostic accuracy studies = 2Prevalence studies = 9

Includ

ed

Studies included in qualitative synthesis (n = 17)

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StudyID

Author  Year  Country Sample size

Index Test

1 Cl 2010 B l i 942 A d1. Clement 2010 Belgium 942 Amrad

2. Lau 2003 USA 2627 Amrad

3. Lien 2000 Vietnam 328 Determine, Dainascreen, Serodia

4. Nakata 1990 NR 300 Hybritech4. Nakata 1990 NR 300 Hybritech

5. Ansari 2007 Iran 240 Acon, Atlas, Intec, Blue Cross, DIMA, Cortez

6. Lin 2008 UK 1250 DRW, Determine

7. Randrianirina 2008 Madagascar 200 Determine, Virucheck, Hexagon, Cypress

8. Kaur 2000 India 2754 Hepacard

9. Akanmu 2006 Nigeria 238 Amrad

10. Oh 1999 Korea 250 Genedia (HBsAg + anti‐HBsAg)

11. Whang 2005 Korea 400 Genedia (HBsAg + anti‐HBsAg), Daewoong (HBsAg + anti‐HBsAg),

12. Cha 2006 Korea 80 SD (HBsAg + anti‐HBsAg), Genedia (HBsAg + anti‐HBsAg), Asan (HBsAg + anti‐HBsAg), 

13. Palmer 1999 Honduras, DR,  298 DetermineTrinidad, Jamaica

14. Davies 2010 Malawi 75 Determine, Onecheck

15 Kh 2010 P ki t 57 O h k A t15. Khan 2010 Pakistan 57 Onecheck, Accurate

16. Torane 2008 India 60 Hepacard

17. Raj 2001 India 1000 Hepacard 7

Quality assessment of studies

QualityQUADAS scores range from 3-10 out of 14. STARD scores range from 7-14 out of 25.Poor to moderate quality

Conflict of interestOnly 2 studies explicitly reported (no Only 2 studies explicitly reported (no

conflict)

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Diagnosing Hepatitis BDiagnosing Hepatitis B• Double stranded DNA virus

HB A f f• HBsAg surface of virus• HBcAg encloses the virus• HBeAg surrounds the core and is a

marker of active replicationmarker of active replication.• Antibodies to HBsAg present with onset

of symptoms.

http://www.hivandhepatitis.com/2008icr/AIDS2008/docs/082208_e.html

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

SubgroupsSubgroups

Index tests detecting:HBsAg: 31 data points

( bb b ) 6 d

True Positives

False positives

False negatives

Truenegatives

• Determine™(Abbott Laboratories): 6 data points

HBsAg + HBeAg (AMRAD Binax Inc ): 7 data pointsHBsAg + HBeAg (AMRAD, Binax Inc.): 7 data points

Antibody to HBsAg: 6 data pointsy g p

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Diagnosing Hepatitis BDiagnosing Hepatitis B

Chronic Hepatitis B diagnosisAcute Hepatitis B diagnosis

IgM anti‐HBcAg +ANDAnti‐

HBsAg ‐

HBsAg + OR   HBV DNA + ORHBeAg +At least 6 months 

HBsAg +  OR HBeAg + OR HBV DNA +

HBsAg + HBcAg+ IgM Anti‐HBcAg +

apart  OR

HBV DNA +

11http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf

Forest plots - SensitivityForest plots Sensitivity

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Forest plot - Specificity

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Bayesian meta-regressionBayesian meta regressionProgram in R: Hierarchical 

Assuming perfect referenceStandard (100%)

Assuming imperfect reference standard (<90‐

model ( ) (

100%)

Subgroup Sensitivity (95% CI)

Specificity (95% CI)

Sensitivity (95% CI)

Specificity (95% CI)

HBsAg 94.76% (90.08‐98.23%)

99.54% (99.03‐99.953%)

96.77% (92.92‐99.26%)

99.89% (99.55‐100%)

Determine ‐HBsAg

98.24% (94.74‐99.98%)

99.96% (99.31‐100%)

98.76% (94.67‐99.99%)

99.94% (99.49‐100%)

A d HB A 95 47% 99 81% 98 04% 99 95%Amrad – HBs+eAg 95.47% (88.88‐99.44%)

99.81% (99.33‐100%)

98.04% (93.39‐99.83%)

99.95% (99.71‐100%)

Anti HBs 93 15% 93 08% 99 77% 96 08%Anti‐HBs  93.15% (85.04‐98.5%)

93.08% (81.9‐99.99%)

99.77% (94.18‐100%)

96.08% (86.38‐100%) 14

ConclusionConclusion• Studies use different and imperfect reference standards,

different samples (oral and blood) testeddifferent samples (oral and blood) tested.

• Variability in study design and reporting quality. y y g p g q yIncomplete reporting of conflict with industry.

Wh h ib d d i ?• What are the antibody tests detecting?

• Lack of research on secondary testing outcomes• Lack of research on secondary testing outcomes

• Most studies conducted in developing countries, role in p g ,developed countries was unclear

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POC tests for Hepatitis Cp

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Hepatitis C - BackgroundHepatitis C Background• WHO estimates

that 170 million that 170 million people worldwide are infected with the Hepatitis C virus (HCV)virus (HCV).

• 70-90% of those infected go on to gbecome chronic carriers.

• HCV is a Single• HCV is a Single-stranded RNA virus

17http://www.hepatitis.org/hepcslides/POWERPOI.PPT/01PVANDA/sld005.htm

DiagnosisCDC algorithm CDC algorithm

IgM Anti HepatitisIgM Anti‐Hepatitis A and Hepatitis B ‐

Anti‐HCV + (EIA) HCV Recombinant 

ImmunoblotAssay  +

Nucleic acid testing for HCV 

RNA +

18http://www.cdc.gov/ncphi/disss/nndss/casedef/hepatitiscacutecurrent.htm

Objective

T th i th il bl id di ti To synthesize the available evidence on diagnostic accuracy of rapid tests for Hepatitis C

To rate the quality of studies using the QUADAS and STARD checklists for diagnostic accuracy.g y

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SearchSearchRecords identified through database searching 

(n =215)

ion

Iden

tificat

Records after duplicates removed (n = 168)

EXCLUDED based on title and abstract:  118

Screen

ing

Not Hepatitis C = 51Other outcomes= 50Prevalence = 17

Eligibility

Full‐text articles assessed for eligibility 

(n = 50)Full‐text articles excluded (n =43)Not rapid tests = 32Reviews = 5

clud

ed

Reviews = 5Not relevant = 5

Studies included in qualitative synthesis 

(n = 7)

Inc (n   7)

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ResultsResultsStudy ID Author Year Country Sample 

SiIndex Test

Size

1. Lee 2010 USA  571 Oraquick

2. Daniel 2005 India 5290 HCV Tri‐Dot

3. Kaur 2000 India 2754 HCV Bidot

4. Montebugnoli 1999 Italy 100 Therma Ricerca

5. Yuen 2001 China 195 SM‐HCV5 ue 00 C a 95 S C

6. Khan 2010 Pakistan 136 Onecheck, Accurate

7 Torane 2008 India 60 Goldspot7. Torane 2008 India 60 Goldspot

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QualityQ y

QUADAS score ranged from 7-10 out of 14.Q g

STARD scores ranged from 8 12 out of 25STARD scores ranged from 8-12 out of 25.

O l d (Kh l 2010) d h h Only one study (Khan et al. 2010) reported whether test readers were blinded.

Conflict of Interest: Lee et al.’s study on Oraquick® –financial relationship with OraSure Technologies Inc

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financial relationship with OraSure Technologies, Inc.

ResultsResults

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ResultsResultsResults Including Oraquick study (Lee et al. 2010)

Assuming perfect reference standard Assuming imperfect reference standard

Sensitivity (95%CI) Specificity (95% CI) Sensitivity (95%CI) Specificity (95%CI)

91 5% (89 7‐93 1%) 99 6% (99 5‐99 8%) 92 72% (72 11‐ 99 88% (99 56‐91.5% (89.7 93.1%) 99.6% (99.5 99.8%) 92.72% (72.1199.93%)

99.88% (99.56100%)

l l d k dResults excluding Oraquick study

Assuming perfect reference standard Assuming imperfect reference standard

Sensitivity (95%CI) Specificity (95% CI) Sensitivity (95%CI) Specificity (95%CI)

72.38% (36.66‐98.2%)

99.88% (98.62‐100%)

77.11% (45.49‐99.61%)

99.99% (99.82‐100%)

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Hepatitis C - ConclusionHepatitis C ConclusionPopulations and countries• No studies in co-infected populations• Majority of evidence from developing countries.

Accuracy: Accuracy: • Limited evidence. • Oraquick® appears to be best but conflict of interest with

industryindustry.

Lack of differentiation between acute and chronic cases.

No research on secondary outcomes

In comparison to HIV, Syphilis, Hepatitis B, HCV tests have a long p , yp , p , gway to go.

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ACKNOWLEDGENTS

This work was supported by a Knowledge Syntheses grant from the Canadian Institute for Health Research. CIHR KRS 102067

Thank you!Dr. Rosanna PeelinggDr. Jorge M CajasDr. Christiane ClaessensDr Marina B KleinDr. Marina B KleinDr. Madhukar PaiDr. Gilles LambertDr. Lawrence Joseph ( THANK YOU) Dr Tom Wong Dr. Nitika Pant Pai

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