Annex 5.3 PICO 1 - How To Test (HBV) Diagnostic Accuracy of Tests To Detect Hepatitis B Surface Antigen: A Meta-Analysis and Review of The Literature
Annex 5.3 PICO 1 - How To Test (HBV) Diagnostic Accuracy of Tests To Detect Hepatitis B Surface Antigen: A Meta-Analysis and Review of The Literature
Annex 5.3 PICO 1 - How To Test (HBV) Diagnostic Accuracy of Tests To Detect Hepatitis B Surface Antigen: A Meta-Analysis and Review of The Literature
Ali Amini,* Helen Kelly,* Debi Boeras, Wen Chen, Jane Falconer, Helen Kelly,
Weiming Tang, Joseph Tucker, Olivia Varsaneux, Rosanna Peeling (Team lead)
London School of Hygiene and Tropical Medicine team
*Co-leaders of this review
September 2015
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1. Executive summary
Background: Rapid diagnostic tests are potentially useful tools for the diagnosis of hepatitis B
surface antigen (HBsAg) globally, particularly in low-resource areas. Expansion for global use
depends on their performance characteristics clinically in the field, ultimately with the aim
being to reach low-resource settings and offer cost–efficient screening as an alternative to
laboratory tests.
Objectives: The purpose of this review was to identify quantitative evidence on the clinical
sensitivity1 and specificity of available in vitro diagnostics (hereafter referred to as assays)
used to detect hepatitis B antibody, synthesize the evidence, and inform models.
Methods: Two reviewers independently assessed the quality and extracted data for
estimating accuracy. Meta-analysis was performed. We further performed stratified estimates
based on individual products, HIV status, specimen type, study setting and design.
Results: Thirty-three studies were included using an EIA reference standard. The overall
pooled clinical sensitivity and specificity of rapid HBsAg tests were 90.0% (95% CI: 89.1, 90.8)
and 99.5% (95% CI: 99.4, 99.5), respectively, compared to laboratory-based immunoassay
reference standards. Pooled specificity was comparable and less heterogeneous.
Pooled sensitivity in studies of HIV-positive was lower than in known HIV-negative
patients; 72.3% (95% CI: 67.9, 76.4) compared to 92.6% (95% CI: 89.8, 94.8), respectively.
Pooled sensitivity and specificity in blood donors were 91.6% (95% CI: 90.1, 92.9) and 99.5%
(95% CI: 99.5, 99.9), respectively.
Samples using whole blood specimens (venous or capillary) were 91.7% (95% CI: 89.1,
93.9) and 99.9% (95% CI: 99.8, 99.9) sensitive and specific compared to serum.
Results were comparable for studies performed prior to the past ten years as those
performed since 2005. Estimates of assay sensitivity demonstrated significant heterogeneity
not entirely corrected by sub-analysis, although studies using whole blood specimens (venous
or capillary), and the same reference standard (CMIA) were more robust (tau-squared <1 in all
cases).
The overall pooled clinical sensitivity and specificity of laboratory-based HBsAg tests
were comparable, with 88.9% (95% CI: 87.0, 90.6) and 98.4% (95% CI: 97.8, 98.8) sensitivity
and specificity, respectively, compared to immunoassay state-of-the-art chemiluminescent
microparticle enzyme immunoassays.
Conclusions: Assays for HBsAg detection such as rapid diagnostic tests (RDTs), including those
performed on serum/plasma and capillary whole blood specimens, have good sensitivity and
excellent specificity compared to a reference standard comprising laboratory-based methods
of HBsAg detection. Improvement in sensitivity, or development of innovative testing
strategies could potentially enhance their use as first-line screening globally. Caution in HIV-
1
Unless otherwise specified, sensitivity and specificity refer to clinical and not analytical sensitivity for tests.
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positive individuals is important, while the reassuring accuracy of capillary whole blood
specimens compared to plasma/serum further facilitates use in settings where phlebotomy is
not available.
2. Background
An estimated 240 million individuals worldwide1 are chronically infected with hepatitis B virus
(HBV) and there are an estimated four million acute HBV infections each year. Twenty per
cent to 30% of those with chronic hepatitis B infection will develop cirrhosis2 or
hepatocellular carcinoma,3 leading to approximately 650 000 deaths each year.4 However,
most individuals with chronic HBV infection are not aware of their serostatus, contributing to
delayed diagnosis and complications from advanced disease.5 HBV testing is critically
important in order to refer infected individuals to HBV treatment and care, to refer uninfected
individuals for vaccination, and to mobilize prevention and control efforts.
In March 2015, the World Health Organization (WHO) published the first guidelines
for the prevention, care, and treatment of individuals with chronic HBV infection.5 These
guidelines focused on assessment for treatment eligibility, initiation of first-line therapies,
switching and monitoring. These initial guidelines did not include testing recommendations,
and in particular which tests to use. Given the large burden of HBV in low- and middle-income
settings where there are limited or no existing HBV testing guidelines, there is a substantial
need for HBV testing guidelines.
Chronic HBV infection is defined as persistence of hepatitis B surface antigen (HBSAg)
for at least six months. However, interpretation of HBV serologies is complex. The serologies
most frequently used for HBV testing include HBsAg, total anti-HBc, and anti-HBs. HBV
screening includes both the one-test (e.g. HBsAg) and two-test strategies (e.g. HBsAg followed
by hepatitia B core antibody [HBcAb] or nucleic acid testing [NAT]).
Detection of HBsAg can include rapid diagnostic tests (RDTs) or immunoassays. Rapid
tests developed for screening include solid-phase assays, flow-through, agglutination and
lateral-flow. The majority, however, are immunochromatographic assays. Immunoassays use
different methods for detection of HBsAg using polyclonal or monoclonal anti-HBs antibodies.
Labelling to measure antigen–antibody complexes can include radioactive compounds,
enzymes with a change in colour in solution, or substances emitting light.
Advances in HBV detection technology create new opportunities for enhancing screening,
referral, and treatment. Previous systematic reviews on hepatitis B infection have focused on
immunological responses,6 surveillance of cirrhosis,7 and treatment.8 Existing systematic
reviews9‒11 on hepatitis B testing focused on point-of-care (POC) tests and included tests with
unclear reference standards or those not appropriate for assessing operational diagnostic
accuracy in the field.
3. Objectives
The purpose of this review was to identify quantitative evidence on the sensitivity and
specificity of assays used to detect hepatitis B antibody, synthesize the evidence and inform
models.
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To our knowledge, this is the first study exclusively comparing the clinical
performance of both RDTs and laboratory-based immunoassays, in addition to addressing the
question of accuracy in the context of HIV specifically.
PICO 1 Among persons identified for hepatitis B testing, what is the diagnostic
accuracy of available assays for detecting HBsAg?
O Diagnostic accuracy (sensitivity, specificity, TN, TP, FN, and FP; positive
predictive value, negative predictive value)
As a subanalysis, we also analysed data for studies comparing the accuracy of HBsAg assays
against a nucleic-acid amplification test (NAT) reference standard. This is important given the
importance of reducing transmission during the seroconversion period and in the diagnosis of
occult hepatitis B, where HBsAg may not be detectable and which is more common in HIV
coinfection. [Results in Annex 9.2]
4. Methods
Search strategy and identification of studies
Literature search strategies were developed by a medical librarian with expertise in systematic
review searching. Our search algorithm consisted of the following components: hepatitis B,
diagnostic tests and diagnostic accuracy (see Annex 1). We searched MEDLINE (OVID
interface, 1946 onwards), EMBASE (OVID interface, 1947 onwards), the Cochrane Central
Register of Controlled Trials (Wiley interface, current issue), Science Citation Index Expanded
(Web of Science interface, 1970 onwards), Conference Proceedings Citation Index-Science
(Web of Science interface, 1990 onwards), SCOPUS (1960 onwards), Literatura Latino-
Americana e do Caribe em Ciências da Saúde (LILACS) (BIREME interface) and WHO Global
Index Medicus. The search was supplemented by searching for ongoing studies in WHO’s
International Clinical Trials Registry.
In addition to searching databases, we contacted individual researchers, experts
working in the field and authors of major trials to address whether any relevant manuscripts
are in preparation or in press. The references of published articles found in the above
2
For convenience we shall refer to all laboratory-based immunoassays for HBsAg detection (ELISA, MEIA, ECLIA,
CMIA) as EIAs as most have some form of enzymatic amplification.
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databases were searched for additional pertinent articles. The review was registered in
PROSPERO and reported in accordance with PRISMA guidelines.
Study selection proceeded in three stages. First, titles/abstracts were screened by a
single reviewer (AA/HK) according to standard inclusion and exclusion criteria. Second, all
articles identified for full manuscript review were obtained and assessed independently by the
two reviewers (AA and HK) against inclusion criteria. Papers were accepted or rejected and
reasons for rejection were specified. Third, discrepancies were resolved by discussion
between review authors, with several studies resolved by a third independent reviewer (RP).
Selection criteria
Types of studies
We included case–control, cross-sectional, cohort studies and randomized trials with a
primary purpose of evaluating HBsAg tests published until May 2015. We excluded:
conference abstracts, comments or review papers; studies with primary aims other than
evaluation of both sensitivity and specificity of HBsAg detection; studies related to disease
prevalence, drug resistance, genotyping, sequencing, or non-diagnostic purposes; studies that
focus on detection of anti-HBsAg (antibody to hepatitis B antigen); articles in languages other
than English.
Participants
We included studies using original data from patient specimens in defined populations. We
included all age groups, settings, countries and specimen types, notably whole blood (venous
and capillary), plasma or serum. Saliva specimens were considered, but no suitable studies
were identified. We excluded studies using commercial reference panels or clinical panels not
sourced by authors given applicability and bias concerns from unknown sampling in unclear
populations.
Index tests
Studies utilizing commercially available HBsAg tests were eligible for inclusion. We excluded:
in-house developed tests; laboratory-based immunoassays which are no longer commercially
available. We did not, however, exclude rapid tests based on current commercial availability,
in keeping with the methodology in recent systematic reviews. We did however sub-
categorize more recent studies between 2005 and 2015.
Reference standard
The reference standard for definite diagnosis of hepatitis B is complicated, given the different
viral kinetics of HBsAg and HBV DNA. We included studies using an established commercially
available immunoassay as a reference standard for HBsAg detection. Studies using a NAT
reference standard were included as a supplementary secondary analysis. For studies
comparing immunoassays, we only included studies using chemiluminescent microparticle
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immunoassays (CMIAs) as the reference standard, given the generally accepted higher
analytical sensitivity of these assays. For studies of rapid tests, in keeping with previous
systematic reviews, we did not limit based on type of immunoassays.
Data extraction
Information on the following variables were independently extracted by the two review
authors (AA, KH): first author, total sample size, country (and city) of sampling, specimen type
(oral fluid, capillary [finger-prick] whole blood, venous whole blood, etc.), eligibility criteria,
reference standard, manufacturer, raw cell numbers (true positives, false negatives, false
positives, true negatives), HIV coinfection, sources of funding, reported conflicts of interest.
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type; patient type (blood donors); patient HIV status. We did not formally test for publication
bias. Where meta-regression was not possible for covariates, we performed descriptive
statistics.
Meta-analysis of the collected data was conducted using the software: Meta-Disc© version
1.4.7. Statistical analysis was performed using Meta-Disc 1.4 for Windows (XI Cochrane
Colloquium, Barcelona, Spain). QUADAS-2 analysis was performed using Microsoft Excel.
5. Results
Study selection
A total of 11 589 citations were identified and 6575 duplicates were removed. Each of the
5014 titles was examined according to pre-specified inclusion and exclusion criteria. A total of
33 research studies were included in the final primary analysis (Fig. 1), with studies comparing
both rapid diagnostic tests (RDTs)14–42 and enzyme immunoassays43–46 against an immunoassay
reference standard. Of these, 19 studies14–31, 47 were also included in a recent systematic
review by Khuroo et al.;11 eight papers from that study were excluded as they were
conference abstracts or letters to editors,48–50 foreign language articles,51, 52 or evaluated
reference panels.53 Two reports by WHO and the International Consortium for Blood Safety
(ICBS) were also excluded as they were not published in peer-reviewed journals and were
case–control studies constructed using reference panels from populations of affected
individuals. Our search identified 11 additional articles32–42 comparing RDTs against the EIA
reference standard not found in the previous review. Six articles exclusively assessed accuracy
in cohorts of HIV-positive individuals.20, 36–38, 54, 55
Studies evaluating laboratory-based immunoassays for HBsAg detection as the index
test all used state of the art CMIAs as the reference standard. Seven studies were included in
the supplementary analysis assessing diagnostic accuracy of HBsAg assays against a nucleic-
acid based reference standard.47, 54–59
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Fig. 1. PRISMA flow diagram outlining study selection examining diagnostic accuracy of
HBsAg assays in our systematic review
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Study characteristics
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Table 1a. Study characteristics – EIA vs EIA
Study Location Sample Study Setting Sample Assay under evaluation Reference standard
3 3
[Author, Year] [Country, City] size design [Type, Brand] [Type, Brand]
Liu, 2014 China 250 CC Hospital patients; outpatients Serum ECLIA, Cobas CMIA, Architect HBsAg
(preselected based on CMIA quantitative ELISA, Wantai
results)
Peng, 2011 China 498 CC Hospital patients Serum ELISA, KHB CMIA, Architect HBsAg
(preselected based on S/CO from KHB
screen)
Geretti, 2010 Ghana, Kumasi 838 CS – CSQ HIV clinic (1/3 on lamivudine) Serum CMIA, Architect HBsAg CMIA, Architect/ Liaison
*
CMIA, Liaison Ultra EIA, Murex v3
EIA, Murex v3
Ol, 2009 Cambodia 120 CS – CSQ Blood donors (rural community) Serum ELISA, Monolisa CMIA, Architect HBsAg
Viet, 2012 Vietnam 119 CS – CSQ Blood donors (rural community) Serum EIA, Monolisa Ultra CMIA, Architect HBsAg
3
Abbreviated names for table clarity – full product names in Annex
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Table 1b. Study characteristics – RDT vs EIA
Study Location Sample Study Setting Sample RDT under Reference test
[Author, Year] [Country, City] size design evaluation [Type, Brand]
[Type, Brand]
Mvere, 1996 Zimbabwe 206 CS Blood bank S Dipstick (PATH) EIA, Auszyme
SimpliRed
Abraham, 1998 India, Vellore 50 CC – Panel Hospital patients (Multiply transfused; chronic liver disease; preop and S QuickChaser EIA, Auszyme or Hepanostika
antenatal patients) Virucheck
400 CS –Screen
Oh, 1999 Korea 250 CC – Panel Blood donor panel S Genedia EIA, Cobas Core
Serodia
Kaur, 2000 India 2754 CS – CSQ Hospital surgery patients; blood donors; patients ruling out HBV S Hepacard EIA, Ortho 3rd generation
Lien, 2000 Viet Nam 328 CC High-risk volunteers; pregnant women; patients with other infectious SP Dainascreen EIA, Monolisa
diseases (including 10 with HIV); preselected HBsAg pos (101), HBsAg Determine MEIA for discordant
neg (99) Serodia
Raj, 2001 India, Vellore 999 CS Hospital laboratory samples (emergency preop screening; antenatal S Hepacard EIA, Auszyme
women in labour; haemodialysis; urgent donor screening) MEIA, AxSYM v2
Clement, 2002 Belgium 942 CC Hospital - patients with biopsy-proven HBV; healthy volunteers from a WB, S BinaxNOW MEIA, AxSYM v2
vaccine evaluation trial; blood donors
Lau, 2003 USA 1011 CS – CSQ Hepatology clinics S fresh Binax NOW EIA, ETI-MAK2
625 CS – CSQ Chinese community health fair (random patients); known HBV-positive WB
patients (liver clinic)
Akanmu, 2006 Nigeria, Lagos 101 CS – CSQ Blood donors (male) WB Binax NOW ELISA, Monolisa
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36 Chronic liver disease
Nyirendra, 2008 Malawi 194 CS – CSQ Hospital Hospital patients including 152 HIV+ P Determine EIA, Bioelisa
Neutralisation (positives)
Lin, 2008 China 671 CC Blood donors (500); Clinical specimens HBsAg+ (171) S Determine EIA, Hepanostika Ultra
DRW
Guinea 579 CC Blood donors (491); Stored positives (88) SP
Ola, 2009 Nigeria 25 CS - CSQ Medical clinic WB AMRAD GWHB ELISA, Wellcozyme Kit
Davies, 2010 Malawi 75 CS – CSQ HIV-positive adults (ART naive) S Determine EIA, Biokit
Neutralization (positives)
Bjoerkvoll, 2010 Cambodia 1200 CS – CSQ General screen – blood donors (rural) S ACON EIA, Monolisa Ultra*
Geretti, 2010 Ghana, Kumasi 838 CS – CSQ HIV clinic (1/3 on lamivudine) S Determine CMIA, Architect/ Liason
VIKIA EIA, Murex v3
Hoffman, 2012 South Africa 973 CS – CSQ HIV-positive adults (ART naïve) – antenatal or primary care WB (cap) Determine ELISA, AxSYM
Bottero, 2013 France, Paris 2472 CS – CSQ General screening (health-care centres) [general population WB (ven) Determine ELISA, Monolisa Ultra
prevention, screening, vaccination] Neutralization (positives)
3922 QUICK PROFILE
3928 VIKIA
Chameera, 2013 Sri Lanka 50 CS Hospital (surgical, other) S Cortez EIA, Surase B-96 (TMB)
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Onsite
Franzeck, 2013 Tanzania, 272 CS – CSQ HIV clinic (ART naive) WB (ven) Determine EIA, Murex v3
Ifakara P Neutralization (positives)
Chevaliez, 2014 Unclear 558 CC Chronic hep B (known mutants, blood donors); HBsAg negative (mix, SP DRW v2.0 CMI, Architect
including HIV, 34; HCV, 48)
Erhabor, 2014 Nigeria, Sokoto 130 CC Blood donors SP ACON ELISA, HBsAg Ultra
Gish, 2014 Australia, 297 CS – CSQ At risk health fairs, outreach; Vietnamese (72%) S Nanosign EIA, Quest Diagnostics
Melbourne
Honge, 2014 Bissau 438 CS – CSQ HIV clinic - mixed ART/ naive S VEDA LAB CLIA, Architect
Liu, 2014 China 250 CC Hospital patients; outpatients S Intec One Step CMIA, Architect
(preselected based on CMIA quantitative results)
Mutocheluh, Ghana 150 CS – CSQ Blood donors P Abon ELISA, Human Gesellschaft
2014 Acull-Tell
Core TM
Rapid care
Wondfo
Upretti, 2014 Nepal 347 CS – CSQ Children – pre- and post vaccination; mothers (8) S SD Bioline EIA, Surase B-96 (TMB)
Njai, 2015 Gambia 178 CS Hepatitis patients CHB carriers (study 3), incl 3 coinfected HIV S Determine CMIA (quantitative),
(treatment naive) Architect
203 Espline
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Assessment of the quality of the studies
Patient selection
We judged 15 studies to be at “high risk of bias”. Of these, 10 were case–control studies.
Others with a high risk of bias included studies in blood donors and highly selected
populations, such as patients with known hepatitis B.
Applicability was judged to be “high risk” in 8 studies, notably those published over
ten years ago or with tests which are no longer commercially available.
Index test
We judged 7 studies as high risk of bias, and 14 as unclear, with the most common reason
being a lack of reported blinding while reading test results.
Reference standard
We judged 5 studies as high risk of bias, with 17 unclear; the most common reason was a lack
of reported blinding interpreting reference tests, or utilisation.
4
Studies refers to either entire articles or individual sub-studies within a single publication using different
patients, methods, index tests or reference standard.
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Table 2. Risk of bias and applicability according to QUADAS-2 domains for individual studies
Patient Index test Reference Flow and Patient Index test Reference
selection standard timing selection standard
Lau (Hepatology clinic) Low Low Low Low Low Unclear Low
Lau (Screen + Known) Low High Low Low Low Unclear Low
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Risk of bias Applicability
Patient Index test Reference Flow and Patient Index test Reference
selection standard timing selection standard
Fig. 2. Risk of bias and applicability summary according to QUADAS-2 domains presented as
percentages across included studies
REFERENCE STANDARD
INDEX TEST
PATIENT SELECTION
0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100%
Proportion of studies with low, high or unclear Proportion of studies with low, high, or unclear
RISK of BIAS CONCERNS regarding APPLICABILITY
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Diagnostic accuracy
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with tau-square 0.3748, 0.3299, respectively suggesting acceptable interstudy heterogeneity.
[Fig. 6, Table 9; and Fig. 9 are in the Annex]
Pooled test accuracy for RDTs using whole blood (capillary or venous)
Seven studies15, 16, 20, 24, 28, 37, 40 contributed 11 data points evaluating 5 RDTs with an EIA
reference, using a total 13731 samples, with sample sizes ranging from 25 to 3928 (mean
722). Sensitivities ranged from 75% to 100% with overall pooled sensitivity of 91.7% (95% CI:
89.1, 93.9). Specificities ranged from 99% to 100%, with overall pooled specificity of 99.9%
(95% CI: 99.8, 99.9). Pooled PLR and NLR were 346.64 (95% CI: 157.598, 762.42) and 0.089
(95%CI: 0.058, 0.136), respectively, with tau-square 0.8124, 0.2367, respectively [Table 5; Fig.
18, Annex 9.3.2].
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Ten articles14, 18, 22, 24, 25, 27, 30, 31, 33, 34 contributed 21 data points evaluating 13 RDTs with an EIA
reference, using a total 7258 samples, with sample sizes ranging from 50 to 698 (mean 345).
Sensitivities ranged from 50% to 100% with overall pooled sensitivity of 96.7% (95% CI: 96.0,
97.3). Specificities ranged from 91% to 100%, with overall pooled specificity of 99.3% (95% CI:
99.0, 99.5). Pooled PLR and NLR were 105.16 (95% CI: 48.038, 230.212) and 0.028 (95%CI:
0.010, 0.076), respectively, with tau-square 2.2261, 4.8632, respectively. Of note, one study22
had significantly lower sensitivity for both index tests evaluated, with otherwise sensitivities
ranging from 90% to 100% in remaining studies [Table 5; Fig. 19, Annex 9.3.3].
Pooled test accuracy for RDTs published before and after 2005
Twenty-one articles15‒17, 19, 20, 22, 25, 28, 30, 32‒43 contributed 44 data points evaluating 26 RDTs with
an EIA reference, using a total 25 261 samples, with sample sizes ranging from 25 to 3928
(mean 574). Sensitivities ranged from 50% to 100 % with overall pooled sensitivity of 86.4%
(95% CI: 85.2, 87.5). Specificities ranged from 69% to 100%, with overall pooled specificity of
99.4% (95% CI: 99.2, 99.5). Pooled PLR and NLR were 84.657 (95% CI: 43.553, 164.553) and
0.126 (95%CI: 0.087, 0.183), respectively, with tau-square 4.0986, 1.2712, respectively.
Nine articles published before 200514, 18, 21, 23, 24, 26, 27, 29, 31 contributed 19 data points
evaluating 10 RDTs with an EIA reference, using a total 25 253 samples, with sample sizes
ranging from 25 to 3928 (mean 1122). Sensitivities ranged from 77% to 100% with overall
pooled sensitivity of 96.9% (95% CI: 96.0, 97.7). Specificities ranged from 97% to 100%, with
overall pooled specificity of 99.7% (95% CI: 99.6, 99.8). Pooled PLR and NLR were 265.5 (95%
CI: 106.1, 664.5) and 0.056 (95%CI: 0.033, 0.095), respectively, with tau-square 2.72, 0.91,
respectively. [Table 5; Figs 21 and 22, Annex 9.3.4]
Determine HBsAg was evaluated in the most studies, with only one published before 2008.
Ten articles16, 19, 20, 24, 25, 30, 36, 37, 40, 41 contributing 12 data points evaluated against an EIA
reference, using a total 7553 samples, with sample sizes ranging from 75 to2472. Sensitivities
ranged from 56% to 100% with overall pooled sensitivity of 90.8% (95% CI: 88.9, 92.4).
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Specificities ranged from 69% to 100%, with overall pooled specificity of 99.1% (95% CI: 98.9,
99.4). Excluding one particularly anomalous study,41 the lowest sensitivities and specificities
would be 69% and 93%, respectively. Pooled PLR and NLR were 239.24 (95% CI: 17.139,
33339.4) and 0.077 (95%CI: 0.035, 0.168), respectively, with tau-square 20.17, 1.556,
respectively. [Table 5, 6]
BinaxNOW HBsAg was evaluated in three articles, (15, 18, 23) all published before
2007, contributing 6 data points evaluating against an EIA reference, using a total 3550
samples, with sample sizes ranging from 36 to 1011. Sensitivities ranged from 94% to 100%
with overall pooled sensitivity of 97.6% (95% CI: 96.2, 98.6). Specificity was 100% in all studies,
with overall pooled specificity of 100% (95% CI: 99.7, 100). Pooled PLR and NLR were 221.21
(95% CI: 36.160, 1354.1) and 0.045 (95%CI: 0.016, 0.128), respectively, with tau-square 3.53,
1.20, respectively. [Tables 5, 6]
VIKIA HBsAg was also evaluated in three articles, 16, 36, 40 all published after 2010,
contributing 3 data points evaluating against an EIA reference, using a total 5242 samples,
with sample sizes ranging from 476 to 3928. Sensitivities ranged from 71% to 97% with overall
pooled sensitivity of 82.5% (95% CI: 77.5, 86.7). Specificities ranged from 99.8% to 100%, with
overall pooled specificity of 99.9% (95% CI: 99.8, 100). Pooled PLR and NLR were 1072.3 (95%
CI: 376.082, 3057.2) and 0.108 (95%CI: 0.026, 0.458), respectively, with tau-square <0.005,
1.472, respectively. [Tables 5, 6]
Serodia HBsAg was also evaluated in three articles24, 27, 31 all published before 2000,
contributing 3 data points evaluating against an EIA reference, using a total 1040 samples.
Sensitivities ranged from 71% to 97% with overall pooled sensitivity of 82.5% (95% CI: 77.5,
86.7). Specificities ranged from 99.8% to 100%, with overall pooled specificity of 99.9% (95%
CI: 99.8, 100). Pooled PLR and NLR were 284.91 (95% CI: 71.42, 1136.6) and 0.045 (95%CI:
0.029, 0.069), respectively, with tau-square <0.005, <0.005, respectively. [Tables 5, 6]
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Fig. 3. Forest plots, RDT vs EIA, ordered by [Test, Author]*
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Positive LR (95% CI)
Abon - Mutocheluh 64.00 (8.69 - 471.26)
Accurate - Khan 9.50 (1.37 - 65.71)
ACON - Bjoerkvoll (Camb) 517.87 (129.54 - 2,070.26)
ACON - Bjoerkvoll (Viet) 434.51 (108.57 - 1,739.03)
ACON - Erhabor 10.46 (5.70 - 19.19)
Acull-Tell - Mutocheluh 69.82 (9.55 - 510.36)
AMRAD - Ola 9.32 (0.67 - 129.54)
Binax - Akanmu (BD) 3.72 (0.34 - 41.10)
Binax - Akanmu (CLD) 59.40 (3.74 - 944.36)
Binax - Clement 268.83 (67.41 - 1,072.16)
Binax - Lau (Fresh S) 1,811.52 (113.19 - 28,991.24)
Binax - Lau (Frozen S) 1,448.64 (90.62 - 23,156.72)
Binax - Lau (WB) 1,051.25 (65.81 - 16,793.27)
Biotec - Ola 4.12 (1.39 - 12.18)
Core TM - Mutocheluh 32.00 (7.60 - 134.68)
Cortez - Chameera 53.67 (3.14 - 917.12)
Cypress - Randrianirina 26.35 (10.06 - 69.00)
Dainascreen - Lien 422.20 (26.49 - 6,728.17)
Dainascreen - Sato 608.08 (38.12 - 9,699.86)
Determine - Bottero 4,498.21 (281.12 - 71,976.88)
Determine - Davies (H+) 100.04 (6.34 - 1,578.57)
Determine - Franzeck (H+) 467.38 (29.27 - 7,463.70)
Determine - Geretti (H+) 966.70 (60.39 - 15,473.86)
Determine - Hoffman (H+) 174.94 (64.74 - 472.74)
Determine - Lien 422.20 (26.49 - 6,728.17)
Determine - Lin (China) 959.01 (60.07 - 15,311.15)
Determine - Lin (Guinea) 753.59 (47.21 - 12,030.12)
Determine - Njai (CHB) 14.29 (3.74 - 54.54)
Determine - Njai (Screen) 1,180.48 (73.85 - 18,870.34)
Determine - Nyirendra 1.82 (1.25 - 2.67)
Determine - Randrianirina 214.02 (13.47 - 3,400.91)
Dipstick (PATH) - Mvere 348.00 (21.75 - 5,568.55)
DRW - Lin (China) 120.60 (45.44 - 320.04)
DRW - Lin (Guinea) 771.27 (48.32 - 12,311.21)
DRW v2.0 - Chevaliez (Hep) 74.50 (29.76 - 186.52)
DRW v2.0 - Chevaliez (Preg) 73.38 (30.62 - 175.83)
DRW v2.0 - Chevaliez CC 43.75 (27.08 - 70.69)
Espline - Njai (CHB) 17.85 (4.63 - 68.81)
Genedia - Oh 197.32 (12.43 - 3,133.39)
Hepacard - Kaur 4,996.94 (312.36 - 79,938.56)
Hepacard - Raj 73.30 (39.56 - 135.82)
Hexagon - Randrianirina 26.05 (9.95 - 68.23)
Intec - Liu 73.20 (4.61 - 1,163.40)
Nanosign - Gish (H+) 34.14 (14.80 - 78.75)
Onecheck - Khan 21.03 (1.34 - 329.93)
Onsite - Chameera 69.00 (4.22 - 1,129.19)
QUICK PROFILE - Bottero 347.25 (186.27 - 647.36)
QuickChaser - Abraham CC 54.62 (3.48 - 857.69)
QuickChaser - Abraham CS 146.05 (35.99 - 592.65)
Rapid care - Mutocheluh 69.82 (9.55 - 510.36)
SD Bioline - Upretti 642.22 (40.07 - 10,293.22)
Serodia - Lien 404.24 (25.36 - 6,443.55)
Serodia - Oh 193.30 (12.17 - 3,069.96)
Serodia - Sato 290.53 (41.05 - 2,056.47)
SimpliRed - Mvere 348.00 (21.75 - 5,568.55)
VEDA LAB - Honge (H+) 75.01 (23.99 - 234.59)
VIKIA - Bottero 1,853.68 (463.49 - 7,413.61)
VIKIA - Geretti (H+) 986.53 (61.64 - 15,789.02)
VIKIA - Njai (Screen) 374.40 (52.77 - 2,656.47)
Virucheck - Abraham CC 54.62 (3.48 - 857.69)
Virucheck - Abraham CS 25.07 (13.71 - 45.82)
Virucheck - Randrianirina 52.10 (13.19 - 205.84)
Wondfo - Mutocheluh 75.64 (10.41 - 549.47)
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Negative LR (95% CI)
Abon - Mutocheluh 0.50 (0.33 - 0.77)
Accurate - Khan 0.53 (0.38 - 0.74)
ACON - Bjoerkvoll (Camb) 0.07 (0.03 - 0.14)
ACON - Bjoerkvoll (Viet) 0.18 (0.13 - 0.26)
ACON - Erhabor 0.02 (0.00 - 0.28)
Acull-Tell - Mutocheluh 0.46 (0.29 - 0.72)
AMRAD - Ola 0.08 (0.02 - 0.36)
Binax - Akanmu (BD) 0.09 (0.03 - 0.26)
Binax - Akanmu (CLD) 0.10 (0.01 - 1.41)
Binax - Clement 0.00 (0.00 - 0.02)
Binax - Lau (Fresh S) 0.08 (0.02 - 0.25)
Binax - Lau (Frozen S) 0.06 (0.02 - 0.16)
Binax - Lau (WB) 0.05 (0.02 - 0.13)
Biotec - Ola 0.48 (0.31 - 0.74)
Core TM - Mutocheluh 0.51 (0.33 - 0.77)
Cortez - Chameera 0.42 (0.16 - 1.09)
Cypress - Randrianirina 0.03 (0.01 - 0.10)
Dainascreen - Lien 0.00 (0.00 - 0.07)
Dainascreen - Sato 0.00 (0.00 - 0.05)
Determine - Bottero 0.07 (0.03 - 0.20)
Determine - Davies (H+) 0.02 (0.00 - 0.30)
Determine - Franzeck (H+) 0.06 (0.01 - 0.27)
Determine - Geretti (H+) 0.31 (0.24 - 0.40)
Determine - Hoffman (H+) 0.25 (0.15 - 0.43)
Determine - Lien 0.00 (0.00 - 0.07)
Determine - Lin (China) 0.01 (0.00 - 0.05)
Determine - Lin (Guinea) 0.06 (0.03 - 0.10)
Determine - Njai (CHB) 0.05 (0.02 - 0.11)
Determine - Njai (Screen) 0.12 (0.07 - 0.20)
Determine - Nyirendra 0.64 (0.43 - 0.94)
Determine - Randrianirina 0.03 (0.01 - 0.09)
Dipstick (PATH) - Mvere 0.09 (0.02 - 0.43)
DRW - Lin (China) 0.01 (0.00 - 0.04)
DRW - Lin (Guinea) 0.04 (0.02 - 0.08)
DRW v2.0 - Chevaliez (Hep) 0.00 (0.00 - 0.04)
DRW v2.0 - Chevaliez (Preg) 0.04 (0.01 - 0.26)
DRW v2.0 - Chevaliez CC 0.05 (0.01 - 0.33)
Espline - Njai (CHB) 0.06 (0.03 - 0.12)
Genedia - Oh 0.02 (0.01 - 0.07)
Hepacard - Kaur 0.07 (0.03 - 0.18)
Hepacard - Raj 0.18 (0.07 - 0.43)
Hexagon - Randrianirina 0.05 (0.02 - 0.12)
Intec - Liu 0.50 (0.43 - 0.58)
Nanosign - Gish (H+) 0.27 (0.13 - 0.57)
Onecheck - Khan 0.49 (0.35 - 0.68)
Onsite - Chameera 0.25 (0.06 - 1.01)
QUICK PROFILE - Bottero 0.10 (0.05 - 0.18)
QuickChaser - Abraham CC 0.12 (0.04 - 0.39)
QuickChaser - Abraham CS 0.23 (0.11 - 0.49)
Rapid care - Mutocheluh 0.46 (0.29 - 0.72)
SD Bioline - Upretti 0.06 (0.00 - 0.82)
Serodia - Lien 0.05 (0.02 - 0.11)
Serodia - Oh 0.04 (0.02 - 0.09)
Serodia - Sato 0.04 (0.02 - 0.09)
SimpliRed - Mvere 0.09 (0.02 - 0.43)
VEDA LAB - Honge (H+) 0.38 (0.28 - 0.51)
VIKIA - Bottero 0.04 (0.01 - 0.11)
VIKIA - Geretti (H+) 0.29 (0.23 - 0.38)
VIKIA - Njai (Screen) 0.10 (0.05 - 0.21)
Virucheck - Abraham CC 0.12 (0.04 - 0.39)
Virucheck - Abraham CS 0.22 (0.09 - 0.52)
Virucheck - Randrianirina 0.04 (0.02 - 0.12)
Wondfo - Mutocheluh 0.41 (0.25 - 0.68)
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Key brands of RDT and reference standards used in studies
rd
Kaur, 2000 Hepacard EIA, Ortho 3 generation
nd
Khan, 2010 Accurate ELISA, 2 generation
Onecheck
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Study Test brand (manufacturer) Reference test type, brand (manufacturer)
Page | 212
Fig. 4. Forest plots, EIA vs EIA, ordered by [Test, Author]**
+
**H = HIV positive
Geretti EIA, Murex v.3.0 (Abbott) CMIA and EIA (agreement) or neutralization
Page | 213
Ol ELISA, Monolisa (bioRad) CMIA, Architect (Abbott)
+
*Camb: Cambodia; Viet: Viet Nam; BD: blood donor study; CLD: chronic liver disease study; Fresh S: fresh serum; Frozen S: frozen serum; WB: whole blood; H : HIV positive;
CHB: chronic hepatitis B cohort; Screen: general screen cohort; Hep: acute hepatitis cohort; Preg: antenatal cohort; CC: case–control study; CS: cross-sectional study
+
**H : HIV positive
Page | 214
Table 3. Summary pooled diagnostic accuracy of HBsAg assays using EIA and NAT reference standards
5
Reference Index test Pooled clinical accuracy Likelihood ratios (REM) Heterogeneity
(Tau-squared)
5
REM : Random effects model
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Table 4. Summary pooled diagnostic accuracy of HBsAg assays in patients with known HIV status
Test type HIV status Pooled clinical accuracy Likelihood ratios (REM) Heterogeneity (Tau-squared)
+6
RDT HIV 6 72.3 99.8 193 0.29 0.384 0.0059
(67.9–76.4) (99.5–99.9) (77.4–497) (0.22–0.38)
+
EIA HIV 3 97.9 99.4 167 0.02 <0.005 <0.005
(96.0–99.0) (99.0–99.7) (95.1–294) (0.01–0.04)
HIV–
6
Three studies on ART-naive patients (Hoffman, Davies, Franzeck); two studies from single article (Geretti) in patients who included 1/3 on lamivudine; with one study (Honge) on a mixture
Page | 216
9.1.1.Table 5. Summary pooled diagnostic accuracy of rapid HBsAg assays stratified by study, patient, index and reference tests
Page | 217
n = number of data points
Page | 218
Table 6. Summary pooled diagnostic accuracy of HBsAg assays by brand
Type Brand name Sen (95% CI) Spec (95% CI) Sen (95% CI) Spec (95% CI)
RDT ACON 88.0 (83.4–91.7) 99.4 (99.0–99.7) 92.9 (87.3–96.5) 99.1 (96.6–99.9)
RDT Cortez 60.0 (14.7–94.7) 100 (92.1–100) 79.7 (73.1–85.3) 97.2 (94.0–99.0)
RDT Intec 50.8 (43.3–58.4) 100 (94.9–100) 99.2 (95.4–100) 97.5 (92.9–99.5)
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RDT VIKIA 82.5 (77.5-86.7) 99.9 (99.8-100)
Page | 220
GRADE
Specificity 0.93–1.00
Outcome No. of studies (no. Study design Factors that may decrease quality of evidence Effect per 1000 patients/year Test
of patients) accuracy QoE
Risk of Indirectness Inconsistency Imprecision Publication pre-test pre-test
bias bias probability of 5% probability of 20%
1 2 3 4
True positives 4 studies Cross-sectional (cohort Serious Not serious Serious Serious None 44–48 176–190 ⨁◯◯◯
1234
(patients with HBsAg) 997 patients type accuracy study) Very low
1 2 3
True negatives 4 studies Cross-sectional (cohort Serious Not serious Serious Not None 884–950 744–800 ⨁⨁◯◯
5 1235
(patients without HBsAg) 997 patients type accuracy study) serious Low
40
1. Downgraded by one for risk of bias: all studies were prospective cohort studies , although one was assessed as high risk of bias because patients were pre-selected based from known chronic hepatitis
B patients.
2. Although study was not specifically designed in HIV-negative patients, clear testing and results were included.
3. Downgraded by one for inconsistency: unexplained heterogeneity may arise from differences between studies in specimen condition (serum, whole blood), specimen processing (field vs laboratory),
reference tests (CMIA; EIA on dried blood spots) and study population (e.g. known chronic hepatitis B patients, general community screen).
4. Downgraded by one for imprecision: confidence intervals extend below 90% accuracy, with tau-squared for PLR >1 (indicating substantial heterogeneity).
Question: Should RDTs be used to diagnose HBsAg in HIV-positive individuals?
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Specificity 1.00 (95% CI: 0.99–1.00)
Outcome No. of studies (no. Study design Factors that may decrease quality of evidence Effect per 1000 patients/year Test accuracy
of patients) QoE
Risk of Indirectness Inconsistency Imprecision Publication pre-test pre-test probability
bias bias probability of 5% of 20%
1 2 3 4
True positives 5 studies Cross-sectional (cohort Serious Not serious Serious Serious None 36 (34–38) 145 (136–153) ⨁◯◯◯
1234
(patients with HBsAg) 2566 patients type accuracy study) Very low
1 2 5
True negatives 5 studies Cross-sectional (cohort Serious Not serious Not serious Not None 948 (945–949) 798 (796–799) ⨁⨁⨁◯
6 1256
(patients without HBsAg) 2566 patients type accuracy study) serious Moderate
1. Downgraded by one for risk of bias: all studies were prospective cohort studies of consecutive patients. Studies used different specimens (serum, 2; capillary whole blood, 1; venous whole blood, 1),
reference standards (CMIA, EIA confirmed by neutralization), and had patients with different ART status (four studies ART naive).
20 36 19 37 38
2. Not downgraded for indirectness: all studies performed in cohorts of consecutive patients in Tanzania , Ghana , Malawi , South Africa and Bissau .
3. Downgraded by one for inconsistency with sensitivities ranging from 62% to 100%: unexplained heterogeneity may arise from differences between studies in specimen type, specimen processing and
had very high sensitivities (100%, 96%) while remainder ‒ had low sensitivities (range 62-70%). Tau-squared <1 for studies
19, 20 36 38
study population. Two Studies
19, 20 36‒38
4. Downgraded by one for imprecision: confidence intervals 67.9–76.4%. Two studies had very high sensitivities (100%, 96%) while remainder had low sensitivities (range 62–70%).
5. Not downgraded for inconsistency: specificities ranged from 99% to 100%, with tau-squared <1
6. Not downgraded for imprecision: narrow confidence interval
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Question: Should Determine HBsAg be used to diagnose HBsAg in a global setting?
Outcome No. of studies (no. of Study design Factors that may decrease quality of evidence Effect per 1000 patients/year Test accuracy
patients) QoE
Risk of Indirectness Inconsistency Imprecision Publication pre-test probability pre-test probability of
bias bias of 5% 20%
True positives 12 studies Cohort & case–control type Serious Not serious Very serious2 Not serious None 45 (44–46) 182 (178–185) ⨁◯◯◯
(patients with HBsAg) 7552 patients studies1 Very low2
True negatives 12 studies Cohort & case–control type Serious Not serious Serious3 Not serious None 941 (940–944) 793 (791–795) ⨁⨁◯◯
(patients without HBsAg) 7552 patients studies Low3
25 24 30
1. Lin , Lien and Randrianirina used a case–control design
2. Significant heterogeneity across studies for sensitivity; tau-squared 20.2
3. Heterogeneity exists, but with lower clinical impact; tau-squared 1.56
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6. Discussion
Study findings
Overall, the diagnostic accuracy of 33 RDTs and 8 EIAs were assessed against an EIA reference
standard. Total numbers of patients included 36,131 (RDT vs EIA, figure 3) and 3751 (EIA vs
EIA, figure 4). Both RDTs and EIAs had similar sensitivity and specificity compared to an EIA
reference standard (Table 3).
Clinical sensitivity estimates for both RDTs and EIAs were characterized by statistical
heterogeneity, whereas specificity estimates were less heterogeneous (Figures 3 and 4). This
applied across brands (Table 6). Heterogeneity can be caused by the use of different reference
standards assays, clinical subgroups within the study population, age (children versus adults),
patient status and stage of disease.
Compared to previous systematic reviews, the pooled clinical sensitivity 90.0% (95%
CI: 89.1–90.8) and specificity 99.5% (95% CI: 99.4–99.5) is slightly inferior for RDTs compared
to an EIA reference standard (Table 3). In particular Results were very heterogeneous in terms
of sensitivity (Table 7). Khuroo et al.11 reported 96.7% sensitivity (95% CI: 95.3, 97.7) and
99.7% specificity (95% CI: 98.6, 99.9). Studies included conference abstracts and studies using
reference panels. Shivkumar et al.60 reported a pooled sensitivity 98.2% (95% CI: 94.7, 99.9)
and pooled specificity 99.9% (95% CI: 99.3, 100).
*Sen : sensitivity; Spec : specificity; CI : confidence interval; RDT : rapid diagnostic test; EIA : enzyme immunoassay;
+ –
LR : positive likelihood ratio; LR : negative likelihood ratio; REM : random effects model
When comparing EIAs to newer CMIA (chemiluminescent assays), two standard ELISA/
EIA based assays manufactured in markets with transitioning economies appeared to perform
poorly compared to other assays.4 Of note, data exists for one assay (KHB) using different
signal cut-off ratio’s (S/CO), with improved sensitivity but worse specificity when using the
grey zone (S/CO 0.2–0.99); sensitivity 96.2%, specificity 70.6% compared to sensitivity of
73.8% and specificity of 88.1%.45
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Results for EIAs are more specific but less sensitive when used in conjunction with
manufacturers’ neutralisation assays. In one study,56 Liason HBsAg (Diasorin) had sensitivity
100% and specificity 70% compared to NAT, with improved overall accuracy using with a
neutralisation assay (sensitivity 96%, specificity 100%). This shows the critical need to use the
neutralization step to confirm any HBsAg reactivity observed upon initial testing.
Sub-analyses
HIV
Our results showed that RDTs may be less sensitive in HIV-positive patients. There was still
heterogeneity in terms of results, with one otherwise good quality review finding that
Determine was 96 % sensitive (95% CI: 80,100) and 100% specific (95% CI: 99,100) in this
cohort.20
The difficulty of accurate diagnosis in HIV patients is possibly explained by an
increased incidence of hepatitis B and in particular occult hepatitis B in this cohort. In
Sudanese HIV-positive ART naïve patients, 27% had detectable HBV DNA, with occult hepatitis
B in 15%.61 Among 495 treatment naïve, HIV-infected adults in Cote-d’Ivoire, 13% were HBsAg
positive, 42% isolated anti-HBc positive, and 10% occult hepatitis B only detected by NAT.62
Median HBV DNA level was lower in those with occult HBV compared to those with CHB.
Immune pressure has also been hypothesized to contribute, with Geretti et al. noting
that discrepant results for RDTs were all mutants in their study. The overlapping surface and
polymerase genes in the HBV genome could imply that RT inhibitors (e.g. lamivudine) can lead
to the emergence of variants carrying mutations of both the polymerase and surface genes,
hence avoiding detection by standard HBsAg assays.
Blood Donors
Pre-transfusion screening of blood donations is a major public health challenge in resource-
limited settings, where prevalence rates for TTIs (transfusion-transmissible infections) are
significant. Screening of individuals with RDTs pre-donation have been adopted in areas with
insufficient laboratory capacity.
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Diagnostic accuracy in our review was similar in blood donors compared to the overall
pooled estimates of RDTs, with sensitivity 91.6 % (95% CI: 90.1, 92.9) and specificity 99.5%
(95% CI 99.3, 99.7). Results were very heterogeneous, with one study in particular having very
low sensitivity (~50–60). Two studies comparing EIAs against EIAs in blood donors had higher
accuracy, with pooled sensitivity 99.3 % (95% CI: 96.4, 100) and specificity 90.9 % (95% CI
82.9, 96.0).
A recent multinational assessment accuracy of TTI screening in Africa using both RDTs
and EIAs on an external quality assessment panel found poor overall sensitivity (75.6%) and
specificity (94.5%) for HBsAg detection.63 This was driven by very poor clinical sensitivity
(47.4%) of HBsAg RDTs, which was lower than that for HCV (63.7%) and HIV (72.4%) in this
population. This can be explained by their lower analytical sensitivity, difficulties in transport
and quality assurance, in addition to often studies being performed on smaller scales. In a
Nigerian blood donor study, 10% of 113 HBsAg-negative repeat donors using RDTs were found
to have quantifiable HBV DNA.57 These patients either had acute infection or occult chronic
infection.
In a recent systematic review of studies evaluating RDTs for infectious disease blood
screening in Africa, there was again significant variability in performance.64 RDTs for HBsAg
detection were again identified for suboptimal sensitivities, with questionable suitability,
especially in high prevalence regions. High false negatives could be due to operator error, low
HBsAg levels, assay degeneration or lot variation.
Whole blood
For rapid diagnostic tests, accuracy using whole blood (capillary and venous) was marginally
superior to serum. The accuracy was comparable to that of EIAs using serum; data from the
eight studies (eleven data points) is also less heterogenous (Annex 9.3.2). The significantly
lower sensitivity of RDTs using plasma is possibly explained by the nature of the studies; one
was in a population of blood donors, while the other was initially designed to assess the
accuracy of RDTs in determining HBV and HCV prevalence in a Malawian population with high
HIV-co-infection rates.41 The authors of the latter study hypothesised that local operational
problems or unexpected technical issues were the reason for poor performance in resource-
limited setting. Others have also since suggested that the high HIV-co-infection rate could
have contributed, with suppression of HBV replication using lamivudine containing regiments
potentially hindering affecting detection by RDT.
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Analytical sensitivity of different assays as a source of heterogeneity
We were unable to explain heterogeneity of results using different assays. Very few rapid
tests meet required analytical LOD (0.130 IU/mL) required by regulatory authorities, but
because of insufficient data in studies we were unable to stratify using LOD as a source of
heterogeneity. This is important as it has been suggested that false-negative HBsAg RDTs are
associated with lower HBsAg levels, low viral load, HBsAg mutants, or specific genotypes, in
addition to ART exposure where lamivudine and tenofovir are used. (16, 25, 36, 65)
In a recent fields studies in the Gambia,40 the range of serum HBsAg levels quantified
by CMIA that showed reactivity with RDTs in the field was 26.5–27, 320 IU/mL, with a
statistically significant (P = 0.0002) difference in median HBsAg level (875 IU/mL) compared to
false negatives using RDT’s (median 1.2; range 0.8–25.5 IU/mL). Interestingly significantly
more false-negatives were female (P = 0.05) with lower median ALT levels (P = 0.01). The
laboratory-based study from the same publication in a chronic hepatitis B cohort found a
higher range of HBsAg levels (2.8–124,925 IU/mL) in those testing positive with RDTs, with a
significant difference in median HBsAg levels (7, 482 vs 0.40 IU/mL; P <0.0001) and median
ALT (P = 0.01) between true-positives and false negatives. The lower limit of detection may be
explained by differences in methodology, given the setting (laboratory vs field), reference test
(CMIA vs ELISA) and sample type (dried blood spots vs serum). This suggests that subjects with
false negatives have lower HBsAg levels and inactive disease compared to true-positives,
minimising the impact of reduced sensitivity. Unfortunately, in the single study identified also
assessing LSM, 17% (4/23) subjects with false negative results had evidence of fibrosis and
would require antiviral therapy.
Another study (Bottero et al)16 also found significantly lower median HBsAg in false
negatives vs true positives. [19.5 vs 2351 IU/mL; p=0.0001], with only 4 false negative having
HBsAg >10 IU/mL. HBV DNA was usually below 200 IU/mL. False positives occurred in
vaccinate patients (n=7), and one patient with resolved infection and anti-HBs titre.
Interestingly ALL false negatives were HBcAb positive.
Data exists from large studies of analytical sensitivity using reference, seroconversion,
mutant panels.53, 65, 66 These include specimens from individuals with low antigenaemia, such
as early infection. Unfortunately, studies of analytical sensitivity of EIAs are conflicting. One
study suggested that 9 out of 10 EIAs were able to detect HBsAg levels as low as 0.2 IU/mL
irrespective of genotype.67 Another comparing newer EIAs (Advia Centaur; Monolisa Ultra;
Liasion; Vidas Ultra) using reference and mutant panels found a lower limit of detection
<350IU/mL, but with varying sensitivity for mutant detection (37.1%–91.4%).68 The authors
hypothesised that the lack of detection was due to epitope recognition of the anti-HBs assay
reagents in the capture phase and in conjugates. Another study assessing 13 different assays
with mutant panels found a range of LOD (0.011-0.096 IU/mL) and sensitivity (63%–98%) in
mutants. Another study found comparable analytical sensitivity between four EIAs but
significant differences in detection of mutants between assays.69 One blood donor study in
China found a significant difference in sensitivities and mutant detection capabilities amongst
assays used by blood banks, with the urgent recommendation of a list of high sensitivity
assays for blood bank screening.70
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In blood donors, studies have found some correlation between HBsAg levels (IU/mL)
and NAT (copies/mL).71 The obvious benefit of more sensitive assays with lower limits of
detection would be improved detection of those with occult hepatitis B or in the early window
period of sero-conversion.
It has been suggested that utilizing “grey zones” in EIAs could improve sensitivity and
allow combination of tests to develop of economic testing strategies.45 Sensitivity improved
from 76–88% to 96–97%, with a further increase to 99% when combining the use of two EIAs.
Studies looking at RDTs using clinical panels have found sometimes conflicting results.
One study found equivalent specificities but significant differences in assay sensitivity
between Uni-Gold™ HBsAg and Determine HBsAg.72
Interestingly, studies in Cambodia and Viet Nam by the same group produced
different results for sensitivity, suggesting uncontrolled variables, such as prozone effect and
genotype variations. The prozone effect may explain why some true positives turned out
negative with rapid tests. Given that specificity is excellent but sensitivity is low suggests that
this is genuine poor performance.
Significant strengths of this meta-analysis include the global evidence base, rigorous pre-
specified protocol incorporating numerous major scientific databases, in addition to review of
the related literature, notably occult hepatitis B and the impact of NAT. We included studies
performed in a range of settings, with a diverse population. We only included studies with
bivariate data, to minimise bias, measuring clinical sensitivity which are more applicable. We
also included evaluations of both RDTs and EIAs, and as such are able to provide a more
comprehensive meta-analysis. Comparing RDTs with EIAs, we were able to identify an
additional 11 studies not found in previous reviews. Incorporation bias was unlikely as all
participants received both index and confirmatory tests independently. As all studies
administered the same reference standard to all patients, which reduces risk of verification
bias. Our study also excluded articles deemed to be high risk of bias or less applicable, such as
conference abstracts or reference panels; reference panels, included in previous reviews, have
higher accuracy than that of tests used in the field but are not as useful in guiding policy.
Accuracy on seroconversion panels do not necessarily reflect the antibody or antigen
spectrum in the populations studied.
Our study, did, however have a number of limitations. First, we only included studies
in English, which potentially introduces publication (language) bias. We will identify relevant
studies in non-English languages from reference lists to address whether this contributed to a
substantial bias or not. Second, a significant proportion of studies were case–control in design
or used preselected cohorts, which would bias results. For example, in well-conducted studies
from the Gambia,40 those in the community setting had a smaller range of HBsAg levels (26.5–
27, 320 IU/mL) than the study conducted in chronic hepatitis B patients (2.8–124,925 IU/mL).
This is one reason for the reduced sensitivity of the same test (Determine HBsAg) in the
screening cohort (88%; 95% CI: 81, 94) compared to the chronic hepatitis cohort (95%; 95% CI:
Page | 228
90, 98) from the same community. Third, some analyses were based on a small number of
studies, which included few positive samples.
There are number of technical and patient factors that could impact accuracy, which
cannot be addressed based on the currently available literature. Specific to hepatitis B
diagnosis, we were unable to correlate the heterogeneity of sensitivity with different stages,
severity and genotypes infection. This was due to insufficient information in studies,
principally additional serology such as HBeAg, anti-HBc IgM, anti-HBc total and anti-HBs
antibodies. Genetic information has long been suspected to impact on diagnostic accuracy,67‒
70, 73, 74
although a recent study of analytical performance found no difference in the detection
of mutants.70, 73‒75 It should be noted that this study was conducted by authors with significant
conflicts of interest. Mutants themselves are also rapidly evolving, such that the prevalence
and type of specific mutants cannot be determined based on historical data, making studies
difficult to organize. Finally, occult hepatitis should also be considered. The addition of NAT
would be useful to stratify patients’ results, but the lack of sufficient of quality studies (Annex
9.2) is testament to the challenges in conducting advanced laboratory based studies in areas
of high disease prevalence. Reference standards are also imprecise, resulting in overdiagnosis
of clinically insignificant disease, and underestimation of diagnostic accuracy of clinically
relevant disease. The natural history of hepatitis B, notably progression and infectiousness, is
being investigated for correlations of quantitative HBsAg, HbeAg and HBV DNA levels. Low
levels of either antigen may not be significant clinically. Short-term spontaneous fluctuations
in DNA and HBsAg are recognized in those with chronic hepatitis B and add extra challenges to
accurate diagnosis with a “gold standard”.76
Statistical heterogeneity was an obvious issue as is often observed in diagnostic
accuracy reviews. Although we performed stratified analyses to identify potential sources,
none fully explained the heterogeneity observed. Firstly, studies evaluated different RDTs,
with rapid changes in technology for both EIAs and RDTs meaning that analytical sensitivity is
variable among the assays evaluated. Although we pooled based on some RDT brands
(Determine HBsAg, BinaxNOW) there were insufficient studies and this pooling did not
entirely account for heterogeneity. Another potential confounder is changes in manufacturing
processes, including components used to manufacture assays Determine, as one example, has
been produced by Abbott, Inverness Medical and Alere Medical Co. Ltd; as the test has been
commercially available for over 10 years, there will undoubtedly be minor product changes.
7. Conclusion
WHO has emphasized the importance of timely global testing, prevention and treatment of
hepatitis B, with predictions of an increasing prominence as a cause of death globally in years
to come. Although RDTs have limitations, many of which can be addressed through improved
training and quality assurance systems, they are frequently the only viable option for
infectious screening in resource-limited settings. Therefore, additional studies and specific
guidelines regarding the use of RDTs in the context of blood safety and patient screening are
needed. In terms of global uptake, lower costs of these assays and ease of use across a variety
of endemic settings is crucial to achieving goals for control of hepatitis. Worldwide, a
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significant proportion of countries are unable to afford quality-assured laboratory-based
testing with enzyme immunoassays; the use of NAT to further reduce the window period of
infection and detect occult hepatitis is beyond reach in many settings at present.
This meta-analysis, along with others, suggests that assays for detection of HBsAg
including RDTs and enzyme immunoassays have the potential to contribute significantly to the
control of hepatitis B globally in endemic areas, which are often include low resource remote
regions. Other benefits of RDTS include easy storage, small sample volumes required with
minimal staff training or additional equipment. Unfortunately, with current issues with poor
clinical and analytical sensitivity and potential difficulties in detection of occult hepatitis B and
mutant variants, a number of cases would be missed. There is also concern that sensitivity is
significantly reduced in HIV-positive patients.
There are numerous difficulties in conducting systematic reviews of the performance
of in vitro diagnostics, particularly in resource-limited settings. There is a significant variation
in terms of quality of studies, most with key parameters missing. Further promotion of current
accepted standards to performing and reporting studies of diagnostic accuracy globally can
help improve the evidence base currently available. Further high quality studies are
desperately needed to assess the accuracy in a variety of settings and support the growing
evidence base for RDTs. Specifically, further studies looking at the impact of different
geographic locations and mutant phenotypes would be invaluable.
From included studies, excellent robust specificity of all assays is reassuring in terms
of ensuring cost–effective initiation of algorithms for further investigation and treatment.
Significant heterogeneity and suboptimal sensitivity of RDTs has to be taken into
consideration as country control programmes consider the trade-off between affordability,
accuracy and accessibility (i.e. ease of use in all levels of the health-care system). The
weighting of these three factors are country specific and could be modelled.
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9. Annexes
9.2. 9.1 Search strategy
Page | 237
35 limit 34 to english language (2345)
Page | 238
36 31 not 35 (3963)
37 limit 36 to english language (3344)
Page | 239
Web of Science
Search was conducted on the Science Citation Index Expanded (1970–20 April 2015) and the
Conference Proceedings Citation Index-Science (1990–20 April 2015).
1 TOPIC: ("hepatitis-b" OR "hep-b" OR (hepatitis near/5 b) OR (hep near/5 b) OR hbv)
(79,505)
2 TOPIC: (hbsag) (12,160)
3 #2 OR #1 (81,526)
4 TOPIC: ((rapid near/5 test) or (rapid near/5 tests) or (rapid near/5 testing) or (rapid
near/5 detect*) or (rapid near/5 diagnos*) or (rapid near/5 screen*) or (rapid near/5 kit)
or (rapid near/5 kits) or (rapid near/5 assay*) or (rapid near/5 device*)) (77,863)
5 TOPIC: (("point of care" near/5 test) or ("point of care" near/5 tests) or ("point of care"
near/5 testing) or ("point of care" near/5 detect*) or ("point of care" near/5 diagnos*) or
("point of care" near/5 screen*) or ("point of care" near/5 kit) or ("point of care" near/5
kits) or ("point of care" near/5 assay*) or ("point of care" near/5 device*)) (5,974)
6 TOPIC: (("near patient" near/5 test) or ("near patient" near/5 tests) or ("near patient"
near/5 testing) or ("near patient" near/5 detect*) or ("near patient" near/5 diagnos*) or
("near patient" near/5 screen*) or ("near patient" near/5 kit) or ("near patient" near/5
kits) or ("near patient" near/5 assay*) or ("near patient" near/5 device*)) (423)
7 TOPIC: ((poc near/5 test) or (poc near/5 tests) or (poc near/5 testing) or (poc near/5
detect*) or (poc near/5 diagnos*) or (poc near/5 screen*) or (poc near/5 kit) or (poc
near/5 kits) or (poc near/5 assay*) or (poc near/5 device*)) (866)
8 TOPIC: ((poct near/5 test) or (poct near/5 tests) or (poct near/5 testing) or (poct near/5
detect*) or (poct near/5 diagnos*) or (poct near/5 screen*) or (poct near/5 kit) or (poct
near/5 kits) or (poct near/5 assay*) or (poct near/5 device*)) (522)
9 TOPIC: ((bedside near/5 test) or (bedside near/5 tests) or (bedside near/5 testing) or
(bedside near/5 detect*) or (bedside near/5 diagnos*) or (bedside near/5 screen*) or
(bedside near/5 kit) or (bedside near/5 kits) or (bedside near/5 assay*) or (bedside
near/5 device*)) (2,705)
10 TOPIC: (radt or radts or rdt or rdts) (1,406)
11 TOPIC: ("rapid test*") (3,783)
12 TOPIC: ("enzyme-linked immunosorbent assay" or ELISA) (141,435)
13 TOPIC: ((enzyme near/2 immunoassay*) or (enzyme near/2 immuno-assay*) or (enzyme
near/2 immunosorbent)) (85,660)
14 TOPIC: ((antigen* near/3 detect*) or (antibod* near/3 detect*)) (56,976)
15 #14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 (286,936)
16 TOPIC: ("diagnos* accura*" or sensitiv* or specific* or valid*) (4,557,124)
17 TOPIC: ("roc curve") (12,767)
18 TOPIC: ("positive predictive value") (23,706)
19 TOPIC: ("negative predictive value") (18,947)
20 #19 OR #18 OR #17 OR #16 (4,566,667)
21 #20 AND #15 AND #3 (1,789)
22 #20 AND #15 AND #3 Refined by: LANGUAGES: ( ENGLISH ) (1,720)
Page | 240
Scopus
Search was conducted on 20 April 2015.
TITLE-ABS-KEY (("heptatitis-b" OR "hep-b" OR (hepatitis W/5 b) OR (hep W/5 b) OR hbv OR
hbsag) AND (((rapid OR "point of care" OR "near patient" OR poc OR poct OR bedside) W/5
(tests OR test OR testing OR detect* OR diagnos* OR screen* OR kit OR kits OR assay* OR
device*)) OR radt OR radts OR rdt OR rdts OR "rapid test*" OR "enzyme-linked
immunosorbent assay" OR elisa OR (enzyme W/2 (immunoassay* OR immuno-assay* OR
immunosorbent)) OR ((antibod* OR anigen*) W/3 detect*)) AND ("diagnos* accura*" OR
sensitiv* OR specific* OR valid* OR "roc curve" OR "positive predictive value" OR "negative
predictive value")) AND (LIMIT-TO (LANGUAGE, "English")) (3,605)
Page | 241
25 "enzyme-linked immunosorbent assay" or ELISA:ti,ab,kw (Word variations have been
searched)
26 #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25
27 MeSH descriptor: [Sensitivity and Specificity] explode all trees
28 diagnos* accura* or sensitiv* or specific* or valid*:ti,ab,kw (Word variations have been
searched)
29 "roc curve":ti,ab,kw (Word variations have been searched)
30 "positive predictive value":ti,ab,kw (Word variations have been searched)
31 "negative predictive value":ti,ab,kw (Word variations have been searched)
32 #27 or #28 or #29 or #30 or #31
33 #15 and #26 and #32
The search found 64 trials.
Page | 242
Summary data for studies assessing diagnostic accuracy against a NAT-reference standard
Study Location Sample size Study Setting Sample Test under evaluation Reference test
[Author, Year] [Country, City] design [Type, Brand] [Type, Brand]
Ansari, 2007 Iran, Urumieh 240 CC Hospital patients S RDT, ACON qPCR
RDT, Atlas
RDT, Blue Cross
RDT, Cortez
RDT, DIMA
RDT, Intec
Khadem-Ansari, Iran, Urumieh 350 CC – CSQ Hospital patients – S ChLIA, Liaison Rt-PCR
2014 referred as ?HBV
Lukhwareni, 2009 South Africa 192 CC HIV cohort – pre S ChLIA, Elecsys qPCR
ART
Mphahlele, 2006 South Africa 167 (HIV+) CC HIV cohort S EIA, AxSYM Nested PCR
128 (HIV–)
Nna, 2014 Nigeria 113 CS Blood donors P RDT, ACON Nested PCR;
(repeat) qPCR for positive
Olinger, 2007 Nigeria, Ibadan 200 CS Hospital patients – S MEIA, AxSYM v2 rtPCR and nested
liver disease, HIV ChLIA, Elecsys PCR
ELFA, VIDAS Ultra
Seremba, 2010 Uganda 74 (HIV-) CS – CSQ Hospital patients - S RDT, Cortez PCR
83 (HIV+) ED, including HIV EIA, ADVIA
qPCR: quantitative PCR; rtPCR: realtime PCR; ChLIA: chemiluminescent immunoassay; CMIA:
chemiluminescent microparticle enzyme immunoassay; ECLIA: electrochemiluminescent immunoassay;
EIA: enzyme immunoassay; ELFA: enzyme-linked fluorescent assay; ELISA: enzyme-linked
immunosorbent assay; MEIA: microparticle enzyme immunoassay; RDT: rapid diagnostic test; rtPCR:
real-time PCR; CC: case–control; CS: cross-sectional; CSQ: consecutive patients; LB: lab-based study
Page | 243
Table 9. Summary pooled diagnostic accuracy of HBsAg assays compared to NAT reference
*Sen: sensitivity; Spec: specificity; CI: confidence interval; RDT: rapid diagnostic test; EIA: enzyme immunoassay
+
RDT HIV 1 37.5 (22.7–54.2) 97.7 (87.7–99.9)
–
HIV 2 57.1 (41.0–72.3) 97.2 (93.1–99.2)
+
EIA HIV 3 57.9 (49.8–65.6) 95.8 (92.7–97.8)
–
HIV 2 83.3 (69.8–92.5) 85.7 (79.2–90.8)
Page | 244
Fig. 5. Forest plots, RDT vs NAT, ordered by [Test, Author]
Atlas (William James House) Roto-GENE 3000 Research (Corbet real time PCR) and kit artus (Hamburg)
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Nna ACON (Acon laboratories) Nested PCR
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Fig. 6. Forest plots, EIA vs NAT, ordered by [Test, Author]
Lukhwareni ChLIA, Elecsys (Roche) Nested PCR, High Pure Viral Nucleic Acid assay (Roche)
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Q-PCR, COBAS TaqMan HBV Test 48 assay ()
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Summary Receiver Operating Characteristic (SROC) curves
Symmetric SROC
0.9 AUC = 0.9944
SE(AUC) = 0.0025
Q* = 0.9704
SE(Q*) = 0.0078
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 0.2 0.4 0.6 0.8 1
1-specificity
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Fig. 8. SROC curves for studies comparing RDTs with NATs
Symmetric SROC
0.9 AUC = 0.9974
SE(AUC) = 0.0012
Q* = 0.9816
SE(Q*) = 0.0053
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 0.2 0.4 0.6 0.8 1
1-specificity
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Fig. 9. SROC curves for studies comparing EIAs with EIAs
Symmetric SROC
0.9 AUC = 0.9953
SE(AUC) = 0.0037
Q* = 0.9735
SE(Q*) = 0.0124
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 0.2 0.4 0.6 0.8 1
1-specificity
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Fig. 10. SROC curves for studies comparing EIAs with NAT
Symmetric SROC
0.9 AUC = 0.9379
SE(AUC) = 0.0217
Q* = 0.8748
SE(Q*) = 0.0271
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 0.2 0.4 0.6 0.8 1
1-specificity
Pooled Sensitivity = 0.93 (0.90 to 0.95) Pooled Specificity = 1.00 (0.99 to 1.00)
Chi-square = 4.74; df = 3 (p = 0.1916) Chi-square = 19.96; df = 3 (p = 0.0002)
0 0.2 0.4 0.6 0.8 1 Inconsistency (I-square)
0 = 36.8
0.2% 0.4 0.6 0.8 1 Inconsistency (I-square) = 85.0 %
Sensitivity Specificity
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Fig. 14. Forest plots, EIAs vs EIAs in HIV-positive patients
Specificity (95% CI)
Architect - Geretti 1.00 (0.99 - 1.00)
Liaison Ultra - Geretti 0.99 (0.99 - 1.00)
Murex v3.0 - Geretti 0.99 (0.98 - 1.00)
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Fig. 17. Forest plots, RDTs vs NAT in HIV-negative patients
Sensitivity (95% CI)
ACON - Nna 0.60 (0.36 - 0.81)
Cortez - Seremba (HIV-) 0.55 (0.32 - 0.76)
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Forest plots, analysed by study design
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Fig. 20. Forest plots, RDTs vs EIA in blood donors
Sensitivity (95% CI)
Abon - Mutocheluh 0.50 (0.28 - 0.72)
ACON - Bjoerkvoll (Camb) 0.93 (0.86 - 0.98)
ACON - Bjoerkvoll (Viet) 0.82 (0.74 - 0.88)
ACON - Erhabor 1.00 (0.88 - 1.00)
Acull-Tell - Mutocheluh 0.55 (0.32 - 0.76)
AMRAD - Ola 0.95 (0.76 - 1.00)
Binax - Akanmu 0.94 (0.87 - 0.97)
Biotec - Ola 0.59 (0.41 - 0.75)
Core TM - Mutocheluh 0.50 (0.28 - 0.72)
Determine - Lin (China) 0.99 (0.96 - 1.00)
Determine - Lin (Guinea) 0.94 (0.90 - 0.97)
Dipstick (PATH) - Mvere 0.93 (0.68 - 1.00)
DRW - Lin (China) 0.99 (0.97 - 1.00)
DRW - Lin (Guinea) 0.97 (0.93 - 0.99)
Genedia - Oh 0.98 (0.94 - 1.00)
Rapid care - Mutocheluh 0.55 (0.32 - 0.76)
Serodia - Oh 0.96 (0.91 - 0.99)
SimpliRed - Mvere 0.93 (0.68 - 1.00)
Wondfo - Mutocheluh 0.59 (0.36 - 0.79)
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Forest plots, analysed by study year
Fig. 21. Forest plots, RDTs vs EIA for studies after 2005
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Specificity (95% C
Abon - Mutocheluh 0.99 (0.96 - 1.0
Accurate - Khan 0.95 (0.74 - 1.0
ACON - Bjoerkvoll (Camb) 1.00 (0.99 - 1.0
ACON - Bjoerkvoll (Viet) 1.00 (0.99 - 1.0
ACON - Erhabor 0.91 (0.84 - 0.9
Acull-Tell - Mutocheluh 0.99 (0.96 - 1.0
AMRAD - Ola 1.00 (0.40 - 1.0
Binax - Akanmu (BD) 1.00 (0.03 - 1.0
Binax - Akanmu (CLD) 1.00 (0.89 - 1.0
Biotec - Ola 0.86 (0.64 - 0.9
Core TM - Mutocheluh 0.98 (0.94 - 1.0
Cortez - Chameera 1.00 (0.92 - 1.0
Cypress - Randrianirina 0.96 (0.91 - 0.9
Determine - Bottero 1.00 (1.00 - 1.0
Determine - Davies (H+) 1.00 (0.93 - 1.0
Determine - Franzeck (H+) 1.00 (0.99 - 1.0
Determine - Geretti (H+) 1.00 (0.99 - 1.0
Determine - Hoffman (H+) 1.00 (0.99 - 1.0
Determine - Lin (China) 1.00 (0.99 - 1.0
Determine - Lin (Guinea) 1.00 (0.99 - 1.0
Determine - Njai (CHB) 0.93 (0.78 - 0.9
Determine - Njai (Screen) 1.00 (0.99 - 1.0
Determine - Nyirendra 0.69 (0.62 - 0.7
Determine - Randrianirina 1.00 (0.97 - 1.0
DRW - Lin (China) 0.99 (0.98 - 1.0
DRW - Lin (Guinea) 1.00 (0.99 - 1.0
DRW v2.0 - Chevaliez (Hep) 0.99 (0.97 - 1.0
DRW v2.0 - Chevaliez (Preg) 0.99 (0.97 - 1.0
DRW v2.0 - Chevaliez CC 0.98 (0.97 - 0.9
Espline - Njai (CHB) 0.95 (0.82 - 0.9
Hexagon - Randrianirina 0.96 (0.91 - 0.9
Intec - Liu 1.00 (0.95 - 1.0
Nanosign - Gish (H+) 0.98 (0.95 - 0.9
Onecheck - Khan 1.00 (0.82 - 1.0
Onsite - Chameera 1.00 (0.92 - 1.0
QUICK PROFILE - Bottero 1.00 (1.00 - 1.0
Rapid care - Mutocheluh 0.99 (0.96 - 1.0
SD Bioline - Upretti 1.00 (0.99 - 1.0
VEDA LAB - Honge (H+) 0.99 (0.98 - 1.0
VIKIA - Bottero 1.00 (1.00 - 1.0
VIKIA - Geretti (H+) 1.00 (0.99 - 1.0
VIKIA - Njai (Screen) 1.00 (0.99 - 1.0
Virucheck - Randrianirina 0.98 (0.94 - 1.0
Wondfo - Mutocheluh 0.99 (0.96 - 1.0
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Negative LR (95% CI)
Abon - Mutocheluh 0.50 (0.33 - 0.77)
Accurate - Khan 0.53 (0.38 - 0.74)
ACON - Bjoerkvoll (Camb) 0.07 (0.03 - 0.14)
ACON - Bjoerkvoll (Viet) 0.18 (0.13 - 0.26)
ACON - Erhabor 0.02 (0.00 - 0.28)
Acull-Tell - Mutocheluh 0.46 (0.29 - 0.72)
AMRAD - Ola 0.08 (0.02 - 0.36)
Binax - Akanmu (BD) 0.09 (0.03 - 0.26)
Binax - Akanmu (CLD) 0.10 (0.01 - 1.41)
Biotec - Ola 0.48 (0.31 - 0.74)
Core TM - Mutocheluh 0.51 (0.33 - 0.77)
Cortez - Chameera 0.42 (0.16 - 1.09)
Cypress - Randrianirina 0.03 (0.01 - 0.10)
Determine - Bottero 0.07 (0.03 - 0.20)
Determine - Davies (H+) 0.02 (0.00 - 0.30)
Determine - Franzeck (H+) 0.06 (0.01 - 0.27)
Determine - Geretti (H+) 0.31 (0.24 - 0.40)
Determine - Hoffman (H+) 0.25 (0.15 - 0.43)
Determine - Lin (China) 0.01 (0.00 - 0.05)
Determine - Lin (Guinea) 0.06 (0.03 - 0.10)
Determine - Njai (CHB) 0.05 (0.02 - 0.11)
Determine - Njai (Screen) 0.12 (0.07 - 0.20)
Determine - Nyirendra 0.64 (0.43 - 0.94)
Determine - Randrianirina 0.03 (0.01 - 0.09)
DRW - Lin (China) 0.01 (0.00 - 0.04)
DRW - Lin (Guinea) 0.04 (0.02 - 0.08)
DRW v2.0 - Chevaliez (Hep) 0.00 (0.00 - 0.04)
DRW v2.0 - Chevaliez (Preg) 0.04 (0.01 - 0.26)
DRW v2.0 - Chevaliez CC 0.05 (0.01 - 0.33)
Espline - Njai (CHB) 0.06 (0.03 - 0.12)
Hexagon - Randrianirina 0.05 (0.02 - 0.12)
Intec - Liu 0.50 (0.43 - 0.58)
Nanosign - Gish (H+) 0.27 (0.13 - 0.57)
Onecheck - Khan 0.49 (0.35 - 0.68)
Onsite - Chameera 0.25 (0.06 - 1.01)
QUICK PROFILE - Bottero 0.10 (0.05 - 0.18)
Rapid care - Mutocheluh 0.46 (0.29 - 0.72)
SD Bioline - Upretti 0.06 (0.00 - 0.82)
VEDA LAB - Honge (H+) 0.38 (0.28 - 0.51)
VIKIA - Bottero 0.04 (0.01 - 0.11)
VIKIA - Geretti (H+) 0.29 (0.23 - 0.38)
VIKIA - Njai (Screen) 0.10 (0.05 - 0.21)
Virucheck - Randrianirina 0.04 (0.02 - 0.12)
Wondfo - Mutocheluh 0.41 (0.25 - 0.68)
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Fig. 22. Forest plots, RDTs vs EIA for studies before 2005
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Specificity (95% CI)
Binax - Clement 1.00 (0.99 - 1.00)
Binax - Lau (Fresh S) 1.00 (1.00 - 1.00)
Binax - Lau (Frozen S) 1.00 (1.00 - 1.00)
Binax - Lau (WB) 1.00 (0.99 - 1.00)
Dainascreen - Lien 1.00 (0.98 - 1.00)
Dainascreen - Sato 1.00 (0.99 - 1.00)
Determine - Lien 1.00 (0.98 - 1.00)
Dipstick (PATH) - Mvere 1.00 (0.98 - 1.00)
Genedia - Oh 1.00 (0.96 - 1.00)
Hepacard - Kaur 1.00 (1.00 - 1.00)
Hepacard - Raj 0.99 (0.98 - 0.99)
QuickChaser - Abraham CC 1.00 (0.88 - 1.00)
QuickChaser - Abraham CS 0.99 (0.98 - 1.00)
Serodia - Lien 1.00 (0.98 - 1.00)
Serodia - Oh 1.00 (0.96 - 1.00)
Serodia - Sato 1.00 (0.98 - 1.00)
SimpliRed - Mvere 1.00 (0.98 - 1.00)
Virucheck - Abraham CC 1.00 (0.88 - 1.00)
Virucheck - Abraham CS 0.97 (0.95 - 0.98)
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Negative LR (95% CI)
Binax - Clement 0.00 (0.00 - 0.02)
Binax - Lau (Fresh S) 0.08 (0.02 - 0.25)
Binax - Lau (Frozen S) 0.06 (0.02 - 0.16)
Binax - Lau (WB) 0.05 (0.02 - 0.13)
Dainascreen - Lien 0.00 (0.00 - 0.07)
Dainascreen - Sato 0.00 (0.00 - 0.05)
Determine - Lien 0.00 (0.00 - 0.07)
Dipstick (PATH) - Mvere 0.09 (0.02 - 0.43)
Genedia - Oh 0.02 (0.01 - 0.07)
Hepacard - Kaur 0.07 (0.03 - 0.18)
Hepacard - Raj 0.18 (0.07 - 0.43)
QuickChaser - Abraham CC 0.12 (0.04 - 0.39)
QuickChaser - Abraham CS 0.23 (0.11 - 0.49)
Serodia - Lien 0.05 (0.02 - 0.11)
Serodia - Oh 0.04 (0.02 - 0.09)
Serodia - Sato 0.04 (0.02 - 0.09)
SimpliRed - Mvere 0.09 (0.02 - 0.43)
Virucheck - Abraham CC 0.12 (0.04 - 0.39)
Virucheck - Abraham CS 0.22 (0.09 - 0.52)
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BIOKIT Bioelisa HBsAg 3.0
nd
BIO-RAD MONOLISA AgHBs (2 Gen)
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Diagnostics
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