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. 2022 Jan 4;2022:7348755. doi: 10.1155/2022/7348755

Performance of HCV Antigen Testing for the Diagnosis and Monitoring of Antiviral Treatment: A Systematic Review and Meta-Analysis

Geane Lopes Flores 1, Jurema Corrêa Mota 2, Larissa Tropiano da Silva Andrade 1, Renata Serrano Lopes 1, Francisco Inácio Bastos 2, Livia Melo Villar 1,✉
PMCID: PMC8752229  PMID: 35028317

Abstract

Background and Aims

Active hepatitis C virus (HCV) infection is based on the detection of HCV RNA that it is effective but presents high cost and the need to hire trained personnel. This systematic review and meta-analysis is aimed at evaluating the diagnostic accuracy of HCV Ag testing to identify HCV cases and to monitor antiviral treatment including DAA treatment.

Methods

The studies were identified through a search in PubMed, Lilacs, and Scopus from 1990 through March 31, 2020. Cohort, cross-sectional, and randomized controlled trials were included. Two independent reviewers extracted data and assessed quality using an adapted Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Our primary outcome was to determine the accuracy of HCV Ag detection for the diagnosis, which we estimated using random-effects meta-analysis.

Results

Of 3,062 articles identified, 54 met our eligibility criteria. The studies described cohorts from 20 countries, including 14,286 individuals with chronic HCV individuals. Studies for ECLIA technology demonstrated highest quality compared to studies that used ELISA. The pooled sensitivity and specificity (95% CI) for HCV Ag detection of active HCV infection were 98.82% (95%CI = 98.04%; 99.30%) and 98.95% (95%CI = 97.84%; 99.49%), respectively. High concordance was found between HCV Ag testing and HCV RNA detection 89.7% and 95% to evaluate antiviral treatment.

Conclusions

According to our findings, HCV Ag testing could be useful to identify HCV active cases in low-resource areas. For antiviral treatment, HCV Ag testing will be useful at the end of treatment.

1. Introduction

Diagnosis of hepatitis C virus (HCV) infection is primarily performed through the detection of the HCV antibodies (anti-HCV), although this test does not differentiate past and current infections. Further information requires HCV-RNA testing. The execution of the latter is difficult due to the need to hire trained personnel, the use of specialized equipment, and the high cost of reagents [1, 2].

Early diagnosis of HCV is important to identify acute and chronic cases and to initiate and monitor therapeutic strategy. Due to this, the identification of the infection in its acute phase is very important for a good clinical prognosis [3–5]. From a complementary point of view, considering most infections are asymptomatic and the fast-viral replication during this phase, it is key to detect acute infections in a prompt and reliable way. Mathematical modeling has highlighted the relevance of acute asymptomatic infections for the overall dynamics of HCV [6].

To reduce costs and improve the access, some studies have used HCV Ag in serum or plasma to diagnose hepatitis C infection. HCV Ag appears approximately 2 to 3 weeks after the contact to virus, almost simultaneously as HCV RNA [7]. HCV antigen (HCV Ag) detection test was used to diagnose HCV in several cases, principally among risk population, immunocompromised individuals and patients under hemodialysis due to its low cost and the shorter time required to get its results [8, 9]. HCV Ag test was also used to monitor antiviral response to PEG interferon and direct antiviral agents (DAAs) [10–15].

Although some studies aimed to evaluate HCV Ag testing for diagnosis of HCV and monitor of antiviral therapy, just one systematic review and meta-analysis has been performed to evaluate the utility of HCV Ag for diagnosis [16]. To our knowledge, there has been no study that evaluates simultaneously diagnostic accuracy of HCV Ag to monitor antiviral therapy. We have conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of HCV Ag testing to identify HCV cases and to monitor antiviral treatment including DAA treatment.

2. Materials and Methods

We conducted a systematic review of HCV diagnostic and treatment using HCV Ag test in comparison to HCV RNA detection in accordance with standard PRISMA guidelines (http://www.prisma-statement.org/). Meta-analysis was conducted to evaluate HCV Ag as diagnostic test for HCV infection.

2.1. Search Strategy

The studies were identified through a search in PubMed, Lilacs, and Scopus with the following terms: (“hepatitis C” OR “HCV” OR “hepacivirus” OR “hepatitis C virus” AND “HCVAg” OR “hepatitis C core antigen” OR “HCV antigen” AND “diagnosis” OR “detection” OR “laboratory method” AND (“therapy” OR “treatment” OR “antiviral therapy.”). The search strategy has been performed with the inclusion of articles published up to May 30th, 2020.

2.2. Study Selection

The inclusion and exclusion criteria were established before proceeding to the search and review. The inclusion criteria were as follows: case-control, cross-sectional, cohort, or randomized trial designs; report of HCV Ag detection in serum, plasma, or other biological specimen; report of HCV RNA detection; and studies in English, Portuguese, or Spanish languages. Exclusion criteria were type of article such as editorial comments, reviews, opinion letters, and conference proceedings and studies with insufficient data to estimate the sensitivity and/or specificity of the assay.

The selection of articles for this review study was based carefully on the evaluation of the title and abstract after searching through the keywords, and when an article met the inclusion criteria, the full text was examined and the data extracted.

2.3. Data Extraction

Two independent researchers extracted the data and then cross-checked. When the data were unclear or required assumptions, two other researchers were consulted to reach consensus. The values of TP, TN, FP, and FN corresponding to the test evaluated in each article were extracted, and 2 × 2 contingency tables and calculation of sensitivity and specificity were made. The articles that did not have these necessary data were reported explicitly; we contacted the corresponding author and requested this data. Studies whose requested data were not answered were excluded.

2.4. Quality Assessment

We used the QUADAS-2 standard (Evaluation of the Quality of Diagnostic accuracy studies 2) to assess the quality and risk of bias in the included studies [17]. This method was designed to evaluate diagnostic accuracy studies through 4 main domains (patient selection, index test, reference standard, and flow and time). Each domain was assessed according to the risk of bias (low, high, or unclear), and in the first three domains, concerns about applicability (low, high, or unclear) were also considered. Two independent reviewers assessed the study's characteristics and methodological quality.

2.5. Statistical Analysis

HCV Ag sensitivity was the proportion of samples with a positive HCV RNA test that were also positive on HCV Ag testing. Specificity was the proportion of samples with negative HCV RNA testing that were also negative on HCV Ag testing. Sensitivity and specificity were the primary outcome measures.

Meta-analyses for each HCV Ag test were implemented to calculate the summary statistics, comprising point estimates and their respective 95% confidence intervals (95% CIs) by random-effects model (REM) and study heterogeneity (I2 statistics). Results from the univariate analyses (including all studies) were compared with the pooled estimates from the bivariate analyses where possible. Descriptive analyses were done for index tests with less than four studies and when substantial heterogeneity was evident from the inspection of the forest and summary plots.

Statistical analyses were performed using program R 4.0.2 with the General Package for Meta-Analysis (Package meta version 4.9-6).

3. Results

3.1. Study Selection and Characteristics

The systematic review identified 3,062 citations, of which 54 papers met inclusion criteria after reading abstract and full text papers (Figure 1). Fifty-four papers used HCV Ag for diagnosis of HCV infection, and some of these studies, as they analyzed different groups, are mentioned more than once in Table 1. And 17 of these 54 studies also provided information on HCV Ag for HCV treatment. Only one study [18] depicted in Table 2 had information about employment of HCV Ag for treatment and not for diagnosis, so this study is not mentioned in Table 1.

Figure 1.

Figure 1

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Flow of information and stages of systematic review.

Table 1.

Main characteristic of studies that used HCV Ag testing to evaluate diagnosis of active HCV infection.

Year Author (reference) Country HCV-GT Study HCV Ag assay Gold standard N Sample Correlation HCV Ag to HCV RNA SE (%) SP (%)
Chemiluminescence immunoassays
2019 Bo Feng et al. [39] China 1, 2, and 3 Prospective Architect HCV Ag (Abbott Diagnostics, Wiesbaden Germany) HCV RNA 782 Serum NA 90.6% 96.6%
2019 Łucejko et al. [40] Poland 1 Prospective Architect HCV Ag (Abbott Diagnostics, Wiesbaden Germany) HCV RNA 514 Serum Before r = 0.75; during r = 0.75; after r = 0.15 97.1% 99.6%
2019 Catlett et al. [41] Australia NA Cohort study Architect HCV Ag (Abbott Diagnostics) HCV RNA 186 Plasma/DBS r = .77 (plasma)
r = .82 (DBS)		 98.1-100% (plasma), 90.7-92.5 (DBS) 100% (plasma/DBS)
2019 Perez- Garcia et al. [42] Spain 1a, 1b, 2, 3, and 4 Prospective Architect HCV Ag (Abbott Diagnostics) HCV RNA 124 Serum/plasma r = 0.932 97% 95%
2019 Fan et al. [36] China 1b Retrospective Architect HCV Ag (Abbott Diagnostics, Wiesbaden Germany) COBAS AmpliPrep/COBAS TaqMan HCV test, v2.0 (Roche Molecular Systems, Pleasanton, CA, USA) 135 Serum r = 0.986 80.2% 89.7%
2019 Xiang et al. [43] China 1b, 2a, 3a, 3b, 6a, 1b/3b Prospective Architect HCV Ag (Abbott Diagnostics) System (Roche Diagnostics) 106 Serum r = 0.894 100% NA
2018 van Tilborg et al. [44] Canada 1a, 1b, 1(unspecified), 2, 3, 4, 5, 6 Retrospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (Roche) 10006 Serum r = 0.97 99.0% NA
2018 Nguyen et al. [24] Vietnam NA Prospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan v2 (Roche) 104 DBS r = 0.80 87.2% 100%
2018 Adland et al. [45] United Kingdom 1, 3 Retrospective Architect HCV Ag (Abbott Diagnostics) Abbott RealTime HCV assay (Abbott Molecular, Des Plaines, IL) 305 NA r 2 = 0.3 97.7% NA
2018 Lamoury et al. [28] Australia 1a, 1b, 2, 3a, 6 Prospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 (Roche Diagnostics) 120 Plasma/DBS Plasma r = 0.69 DBS r = 0.65 91.6% plasma and 82.9% DBS 100% plasma and 96.1% no DBS
2018 Chevaliez et al. [14] NA 1b Retrospective Architect HCV Ag (Abbott Diagnostics) Roche High-Pure system/COBAS TaqMan HCV test v2.0 (Roche) 631 Plasma r 2 = 0.7357 99.80% NA
2017 Wasitthankasem et al. [29] Thailand 1a, 1b, 3a, 3b, 6c, 6f, 6i, 6n Transversal Architect HCV Ag (Abbott Diagnostics) Abbott RealTime HCV (Abbott Molecular) 290 Serum r 2 = 0.890 100% 97.1%
2017 Mohamed et al. [27] Tanzania 1a, 4a Prospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 (Roche Molecular) 153 Serum/DBS r = 0.80 99.1% serum and 76.7% DBS 94.4% serum and 97.3% DBS
2017 Lucejko et al. [46] Europe 1a/1b/3a/4-2/29/0/2 Longitudinal Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep HCV test (Roche Molecular Systems, Pleasanton, CA, USA) 33 Serum/plasma r = 0.625 100% NA
2017 Talal et al. [47] EUA 1a, 1b, 2, 3, 4 Prospective Architect HCV Ag (Abbott Diagnostics) COBAS TaqMan assay (Roche Diagnostics) 109 Serum r = 0.88 97.9% 100%
2017 Rockstroh et at [15]. NA 1 Retrospective Architect HCV Ag (Abbott Diagnostics) Roche High-Pure /COBAS TaqMan HCV test v2.0 (Roche Diagnostics) 737 Plasma r 2 = 0.7520 99.05% 100%
2017 Loggi et al. [48] Italy 1a, 1b, 1(subtype not available), 2, 3, 4 Longitudinal Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 (Roche Diagnostics) 96 Serum r = 0.767 100% NA
2017 Arboledas et al. [49] Spain 1a, 1b, 2, 3, 4 Prospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV assay (Roche Diagnostics) 262 Plasma r = 0.83 98.7% NA
2017 Arboledas et al. [49] Spain 1a, 1b, 2, 3, 4 Retrospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV assay (Roche Diagnostics) 132 Plasma r = 0.72 98.5% NA
2017 Lamoury et al. [11] Australia 1, 2, 3 Prospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 (Roche Diagnostics) 92 Plasma rho = 0.89 94% NA
2017 Alonso et al. [50] Spain 1a, 1b, 2c, 3, 4 Retrospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV assay (Roche Diagnostics) 28 Serum NA 96.2% 100%
2016 Aghemo et al. [13] Italy 1, 2, 3, 4, 5 Prospective Architect HCV Ag (Abbott Diagnostics) Abbott RealTime HCV (Abbott Molecular) 58 Serum NA 100% NA
2016 Pischke et al. [51] Germany 1, 2, 3, 4 Retrospective longitudinal Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 (Roche Diagnostics) 20 NA NA 100% NA
2016 Kim et al. [52] South Korea 1, 2 Retrospective Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV assay(Roche Diagnostics) 92 Serum BG∗ r = 0.798 98.9% NA
2015 Kamal et al. [53] Egypt 4 Prospective longitudinal Architect HCV Ag (Abbott Diagnostics) COBAS Amplicor version 2.0 (Roche Molecular) 410 Serum r = 0.944 99.5% 96.8%
2015 Garbuglia et al. [54] Italy 1a, 1b Prospective Architect HCV Ag (Abbott Diagnostics) Abbott RealTime HCV (Abbott Molecular) 23 Plasma/serum Day 0: r = 0.95 day 1: r = 0.79 day 4: r = 0.73 100% NA
2014 Chevaliez et al. [55] NA 1, 2, 3a, 4, 5a, 6 NA Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 (Roche Diagnostics) 514 NA r = 0.89 100% 100%
2014 Garbuglia et al. [56] Italy 1a, 1b, 1c, 1a/b, 2a, 2c/b, 3a, 4a Retrospective Architect HCV Ag (Abbott Diagnostics) Abbott RealTime HCV (Abbott Molecular) 292 Plasma r = 0.815 90.4% 87.5%
2014 Heidrich et al. [57] Germany 1n, 2n, 3n Prospective Architect HCV Ag (Abbott Diagnostics) COBAS TaqMan assay v1.0 (Roche Diagnostics) 596 Serum r = 0.803 92.9% 98.9%
2014 Florea et al. [35] Romania NA Retrospective Architect HCV Ag (Abbott Diagnostics) COBAS TaqMan assay (Roche Diagnostics) 76 Serum r = 0.980 82.4% 100%
2014 Long et al. [26] China 1b, 1a Retrospective longitudinal Architect HCV Ag (Abbott Diagnostics) Abbott RealTime HCV (Abbott Molecular) 227 Plasma HCV: r = 0.595
HCV/HIV-1: r = 0.884		 100% NA
2013 Hadziyannis et al. [58] Greece 1, 2, 3, 4 NA Architect HCV Ag (Abbott Diagnostics) COBAS Amplicor v2.0 (Roche Molecular) 89 Serum r = 0.89 93.2% NA
2013 Tedder et al. [10] UK 1a, 1b, 2, 3 Retrospective Abbott Architect HCV (Abbott Diagnostics) RT-PCR TaqMan in-house 54 Plasma r = 0.6 90.7% NA
2012 Murayama et al. [22] Japan 1a, 1b, 2a, 2b Transversal Architect HCV Ag (Abbott Diagnostics) COBAS AmpliPrep/COBAS TaqMan (Roche Diagnostics) and Abbott RealTime HCV (Abbott Molecular) 80 Plasma r = 0.9393 100% NA
2012 Murayama et al. [22] Japan 1a, 1b, 2a, 2b Transversal Lumipulse Ortho HCV Ag (Fujirebio, Tokyo, Japan) COBAS AmpliPrep/COBAS TaqMan (Roche Diagnostics) and Abbott RealTime HCV(Abbott Molecular) 80 Plasma r = 0.9065 95% NA
2012 Vermehren et al. [59] NA 1a, 1b Prospective Architect HCV Ag (Abbott Diagnostics) Abbott RealTime HCV (Abbott Molecular) 160 Serum (Versant HCV RNA Qualitative Assay) r = 0.91 and ART (Abbott RealTime HCV assay) r = 092 99.3% NA
2012 Mederacke et al. [25] Germany 1a, 3a Transversal Architect HCV Ag (Abbott Diagnostics) COBAS TaqMan assay (Roche Diagnostics) 238 Serum/plasma HIV/HCV r = 0.97 HCV/HBV r = 0.04 HCV/HIV: 95.7% HCV/HBV: 100% HCV/HIV:1100%
HCV/HBV:9100%
2011 Kesli et al. [60] Turkey 1b Retrospective Architect HCV Ag (Abbott Diagnostics) QIAamp viral RNA minikit (Qiagen) 212 Serum r = 0.864 96.3% 100%
2011 Moscato et al. [30] Italy 1a, 1b, 2a, 2c, 3a, 4 Retrospective Architect HCV Ag (Abbott Diagnostics) COBAS TaqMan assay (Roche Diagnostics) 32 Serum r = 0.799 Group A:97.1% group B: 100% GroupA:100% group B: 100%
2010 Miedouge et al. [61] France 1, 1a, 1b, 1d, 2, 2a, 2b, 2c, 2k, 2i, 2r, 2x, 3a, 4a, 4c, 4d, 4r, 5a, 6 Cohort Architect HCV Ag (Abbott Diagnostics) COBAS TaqMan assay (Roche Diagnostics) 3009 Serum r = 0.904 100% 99.2%
2010 Ross et al. [62] Germany 1a, 1b, 2a, 3a, 4a, 5a e 6f Prospective Architect HCV Ag (Abbott Diagnostics) Versant HCV RNA v3.0 (Siemens Diagnostics) 394 Serum r = 0.857 100% 100%
2005 Masahiko Takahashi et al. [32] Japan NA Prospective Lumipulse Ortho HCV Ag (Ortho Clinical Diagnostics) COBAS Amplicor version 2.0 (Roche Diagnostics) 44 Serum r = 0.870 90.9% NA
ELISA
2017 Wang et al. [23] China NA Longitudinal ELISA HCV Ag (LaiBo Biotechnology) Abbott RealTime HCV (Abbott Molecular) 333 Serum r = 0.891 88.9% 100%
2012 Murayama et al. [22] Japan 1a, 1b, 2a, 2b Transversal ELISA-Ag (Ortho Clinical Diagnostics, Tokyo, Japan) COBAS AmpliPrep/COBAS TaqMan (Roche Diagnostics) and Abbott RealTime HCV (Abbott Molecular) 80 Plasma r = 0.9666 100% NA
2012 Murayama et al. [22] Japan 1a, 1b, 2a, 2b Transversal Ortho HCV Ag IRMA (Ortho Clinical Diagnostics, Tokyo, Japan COBAS AmpliPrep/COBAS TaqMan (Roche Diagnostics) and Abbott RealTime HCV (Abbott Molecular) 80 Plasma r = 0.9666 100% NA
2012 Murayama et al. [22] Japan 1a, 1b, 2a, 2b Transversal Lumispot Eiken HCV Ag (Eiken Chemical, Tokyo, Japan) COBAS AmpliPrep/COBAS TaqMan (Roche Diagnostics) and Abbott RealTime HCV (Abbott Molecular) 80 Plasma r = 0.9666 100% NA
2008 Medhi et al. [63] India NA Transversal Orthotrak-C™ (Ortho Clinical Diagnostics) (Ortho HCV 3.0) QIAamp viral RNA minikit (Qiagen) in-house RT-PCR and real-time PCR 250 Serum NA 96% 100%
2006 Reddy et al. [34] India NA Retrospective Ortho HCV Ag (Ortho Clinical Diagnostics) COBAS Amplicor HCV test v2.0 (Roche) 111 Serum NA 60% 83%
2005 Bouzgarou et al. [64] Tunisia 1a, 1b, 2c, 3a, 4c/4d Retrospective Orthotrak-C™ (Ortho Clinical Diagnostics) In-house RT-PCR and COBAS Amplicor Monitor v2.0 (Roche version) 76 Serum NA 84% 89%
2005 González et al. [21] Spain 1 Cohort Orthotrak-C™ (Ortho Clinical Diagnostics) COBAS Amplicor HCV test v2.0 (Roche) and COBAS Amplicor HCV Monitor v2.0; Roche Diagnostics (RNA) 58 Serum r = 0.781 42.5% 100%
2005 Laperche et al. [7] France 1, 1a, 1b, 2a/c, 3a, 4a, 4c/d Cohort Orthotrak-C™ (Ortho Clinical Diagnostics) COBAS Amplicor HCV test v2.0 (Roche) 35 Plasma NA Panel 1 : 100%
Panel 2: 96.3%		 NA
2005 Massaguer et al. [65] Spain 1, 2, 3, 4 Cohort Orthotrak-C™ (Ortho Clinical Diagnostics) COBAS Amplicor HCV test v2.0 (Roche) 116 Serum r = 0.802 92.1% 100%
2005 Fabrizi et al. [66] Italy NA Prospective Orthotrak-C™ (Ortho Clinical Diagnostics) COBAS Amplicor HCV test v2.0 (Roche) 292 Serum r = 0.892 92.7% 97.4%
2004 Soffredini et al. [31] Italy 1a, 1b, 2a/c, 3a, 4c/d Prospective Orthotrak-C™(Ortho Clinical Diagnostics) Versant HCV RNA v3.0 (Siemens Diagnostics) 111 Serum r = 0.750 94% NA
2004 Lorenzo et al. [67] Spain 1a, 1b, 2a/c, 3a Cohort Orthotrak-C™ (Ortho Clinical Diagnostics) COBAS Amplicor HCV test v2.0 (Roche) 16 Serum NA 87.6% 40%
2004 Schütler et al. [20] Germany NA Prospective Orthotrak-C™ (Ortho Clinical Diagnostics) In-house real-time PCR 23 Serum r 2 = 0.744 98% 96.2%
2003 Tanaka et al. [68] Japan 1b, 2a, 2b Retrospective In-house COBAS Amplicor HCV test v1.0 (Roche) 207 Serum r = 0.627 97% 100%
Immunohistochemistry
1997 Ballardini et al. [19] Italy 1a,1b,2,3a,4a Retrospective In-house RT-PCR in-house 31 Liver tissue NA 80.6% NA
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Legend: NA: not available; GT: genotype; SE: sensitivity; SP: specificity; V: version; BG∗: both genotypes; r and rho: correlation coefficient; r2: coefficient of determination.

Table 2.

Main characteristic of studies that used HCV Ag testing to evaluate antiviral treatment.

Year Author Country HCV Ag assay N Treatment Sensitivity Specificity Concordance
2019 Bo Feng et al. [39] China Architect HCV Ag (Abbott Diagnostics) 782 PEG-IFN-α and ribavirin NA NA NA
2020 Lin et al. [18] Architect HCV Ag (Abbott Diagnostics) 110 Paritaprevir/ritonavir, ombitasvir e dasabuvir NA NA Baseline: 97.3, week 2 : 54.8, week 4 : 63.9, end: 89.7, post-W12: 98.6
2019 Fan et al. [36] China Architect HCV Ag (Abbott Diagnostics) 135 (PEG-INF-α) and RBV Week 12: 96.5% Week 12: 79.5% NA
2018 van Tilborg et al. [44] Canada Architect HCV Ag (Abbott Diagnostics) 10.006 Treatment of direct acting antivirals (excluding TVR and BOC) with or without PEG-INF, RBV Week 4: 34.6%
End of treatment: 50%
Follow-up week 12: 98.2%
Follow-up week 24: 100%		 Week 4: 86.6%
End of treatment: 97.5%
Follow-up week 12: 97.7%
Follow-up week 24: 100%		 NA
2018 Chevaliez et al. [14] NA Architect HCV Ag (Abbott Diagnostics) 631 PRV boosted with ritonavir and OBV in a single pill combined with DSV Week 4: 71.0%
Week 12: 96.2%
Posttreatment week 12: 87.5%		 Week 4: 95.3%
Week 12: 97.4%
Posttreatment week 12: 98.9%		 Concordance: 99.84%
Week 4: 97.05%
Week 12: 98.8%
Posttreatment week 12: 99%
2017 Łucejko et al. [46] Europe Architect HCV Ag (Abbott Diagnostics) 33 OBV/PRV/r±DSV±RBV and LDV/SOF Day 7: 62.5%
Week 4: 50%		 Day 7: 44.4%
Week 4: 81.8%
End of treatment: 100%		 NA
2017 Rockstroh et al. [15] NA Architect HCV Ag (Abbott Diagnostics) 737 RTV-boosted PRV and OBV with DSV coadministered with or without RBV NA NA Concordance between HCV Ag and HCV RNA in week 4 (96.46%) and posttreatment week (99.75%)
2017 Loggi et al. [48] Italy Architect HCV Ag (Abbott Diagnostics) 96 3D±RBV; SOF±RBV; SOF+SMV±RBV; SOF+LDV±RBV; SOF+DCV; SOF+PEG-IFN-α+RBV Week 2: 42.8% week 4: 31.25% week 8 and 12: 0% Week 2: 84.2%
Week 4: 78.4%
Week 8: 82.1%
Week 12: 90.4%
Week 16 and 24: 100%		 NA
2017 Arboledas et al. [49] Spain Architect HCV Ag (Abbott Diagnostics) 262 2D+RBV; 3D±RBV; SOF+DAC±RBV; SOF+LED±RBV; SOF+SIM±RBV; SOF+PEG+RBV; SOF+RBV; SIM+DAC+RBV NA NA Week 1: 56.7%
Week 4: 83%
End of treatment: 93.5%
2017 Lamoury et al. [11] Australia Architect HCV Ag (Abbott Diagnostics) 92 PEG-INF-α-2b and RBV Treatment: 31%
Posttreatment: 100%
End of treatment: 56%
SVR12/24 : 100% sensitivity and specificity		 Treatment: 98%
Post treatment: 100%
End of treatment: 100%		 NA
2017 Alonso et al. [50] Spain Architect HCV Ag (Abbott Diagnostics) 28 Viekirax+Exviera/Harvoni/Viekirax+Exviera+RBV/Harvoni+RBV/Sovaldi/SOF+DCV/SOF+SMV+RBV NA End of treatment: 92.8% NA
2016 Aghemo et al. [13] Italy Architect HCV Ag (Abbott Diagnostics) 58 PRV/RTV/OBV+DSV±RBV or SOF+SMV±RBV/SOF+RBV/PEG-IFN associate SOF+RBV/SOF+RBV or SOF+SMV±RBV NA NA Concordance HCV RNA and HCV Ag: week 2: 40%; week 4: 55%; at the end of treatment, as expected, the agreement between the tests raised to 95%.
2016 Kim et al. [52] South Korea Architect HCV Ag (Abbott Diagnostics) 92 PEG-IFN-α-2a Week 4: 33.3% Week 4: 100% NA
2015 Kamal et al. [53] Egypt Architect HCV Ag (Abbott Diagnostics) 410 PEG-IFN-α2a and RBV Week 4: 100%
Week 12: 100%		 Week 4: 97.5%
Week 12: 99.3%		 NA
2014 Florea et al. [35] Romania Architect HCV Ag (Abbott Diagnostics) 1782 IFN+RBV 4 weeks: 77.9%
12 weeks: 52.1%
24 weeks: 48.1%
48 weeks: 88.2%
72 week: 96.1%		 4 weeks: 100%
12 weeks: 100%
24 weeks: 100%
48 weeks: 100%
72 week: 100%		 NA
2005 González et al. [21] Spain Orthotrak-C™ (Ortho Clinical Diagnostics) 58 IFN-α2α+RBV Week 4: 42.5%
Week 12: 10.5%
24 weeks after end of: 88.9%		 EOT week 4: 100%
EOT week 12: 100%
24 weeks after end of: 100%		 NA
2005 Masahiko Takahashi et al. [32] Japan Lumipulse Ortho HCV Ag (Ortho Clinical Diagnostics) 44 PEG-IFN-α-2a+RBV Week 7: 76.9%
Day 15: 74.1%		 NA Week 7: 79.5%; day 15 = 4: 75%
2004 Soffredini et al. [31] Italy Orthotrak-C™ (Ortho Clinical Diagnostics) 111 IFN+RBV Week 12: 70.5%
6 months after therapy: 94.2%		 NA NA
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Legend: PEG: peliguiado; BOC: boceprevir; TVR: telaprevir; DCV: daclastavir; SOF: sofosbuvir; DAC: daclavir; DSV: dasabuvir; LDV: ledipasvir; OBV: ombitasvir; PRV: paritaprevir; RBV: ribavirin; RTV: ritonavir; IFN: interferon; SIM/SMV: simeprevir; NA: not available.

Among the 54 studies that evaluated the detection of HCV Ag for the diagnosis of HCV, most of papers (n = 42) that used the electrochemiluminescence methodology presented high quality. In general, all assays were qualitative, both EIA or ECLIA.

The main characteristics of studies included here are presented in Tables 1 and 2. Papers from 20 countries were published from 1997 to 2019. A total of 14,286 individuals were included in papers that evaluated HCV Ag for diagnosis, and 15,680 individuals were reported in papers that used HCV Ag to monitor antiviral treatment. A total of 49 studies provided information on HCV genotypes in infected individuals.

3.2. Quality Assessment

The overall risk of bias assessment for studies included was evaluated using QUADAS-2 and quality scores of these studies (Supplemental Material, Figures S1, S2, S3). The overall quality of the studies was high where reports using electroquimioluminescence had the best quality. According to figure S2, the risk of bias was higher in the test index.

This was also demonstrated in the individual analysis of the studies (Figure S3). The quality with the ELISA and immunohistochemistry tests, as the index test, proved to be lower [19–23]. And also, two of the three studies evaluated samples of DBS [11, 24].

3.3. HCV Antigen for Diagnosis of HCV Active Infection

In this review, different types of studies were included such as the following: longitudinal, transversal, prospective, retrospective, and cohort. One study included HCV/HBV-coinfected individuals, and two studies enrolled HCV/HIV-coinfected patients [25, 26].

Four studies demonstrated sensitivity values lower than 87.2%, but three of these studies employed dried blood spot (DBS) samples for testing [24, 27, 28]. A total of 15 studies used ELISA as detection method where only three of them reported sensitivity ≤ 60%. Only one study used the immunohistochemistry technique to detect HCV Ag [19]. Table 3 demonstrates sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), correct classification (accuracy), and Kappa for studies.

Table 3.

Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), correct classification (accuracy), and Kappa for studies.

Article SE SP PPV NPV Accuracy Kappa
Lamoury, 2018 [28] 97.7 100.0 100.0 94.1 98.3 97.1
Lamoury, 2018 [28] 88.6 96.9 98.7 75.6 90.8 89.7
Adland, 2018 [45] 94.5 100.0 100.0 90.5 96.4 95.3
Nguyen, 2018 [24] 87.2 100.0 100.0 57.7 89.1 87.8
Wasitthankasem, 2017 [29] 100 97.1 99.1 100.0 99.3 98.0
Alonso, 2017 [50] 96.4 100.0 100.0 96.6 98.2 97.2
Mohamed, 2017 [27] 99.1 94.4 98.3 97.1 98.0 96.7
Mohamed, 2017 [27] 76.7 97.3 98.9 57.1 81.7 80.6
Talal, 2017 [47] 97.9 100.0 100.0 98.4 99.1 98.1
Rockstroh, 2017 [15] 99.5 100.0 100.0 99.4 99.7 98.7
Chevaliez, 2014 [14] 100.0 100.0 100.0 100.0 100.0 98.9
Garbuglia, 2014 [56] 91.4 - 100.0 - 91.4 89.6
Heidrich, 2014 [57] 92.6 98.9 99.6 83.9 94.4 93.2
Mederacke, 2012 [25] 95.7 100.0 100.0 25.0 95.8 93.9
Mederacke, 2012 [25] 100.0 90.9 94.6 100.0 96.5 95.4
Mederacke, 2012 [25] 100.0 100.0 100.0 100.0 100.0 98.9
Yuksel, 2011 [69] 94.3 97.9 99.1 87.0 95.3 94.2
Kesli, 2011 [60] 96.3 100.0 100.0 89.7 97.2 95.9
Moscato, 2011 [30] 100.0 - 97.1 - 97.1 95.2
Moscato, 2011 [30] 100.0 100.0 100.0 100.0 100.0 98.4
Miedouge, 2010 [61] 98.9 100.0 100.0 88.9 99.0 97.3
Ross, 2010 [62] 100.0 100.0 100.0 100.0 100.0 98.8
Medhi, 2008 [63] 96.4 100.0 100.0 86.7 97.1 95.7
Reddy, 2006 [34] 14.3 97.8 60.0 83.0 82.0 80.4
Bouzgarrou, 2005 [64] 83.6 88.9 99.0 29.6 84.0 82.5
Gonzalez, 2005 [21] 68.9 100.0 100.0 74.7 83.8 82.8
Massaguer, 2005 [65] 92.1 100.0 100.0 65.5 93.1 91.7
Fabrizi, 2005 [66] 92.7 97.4 94.7 96.5 95.9 94.8
Lorenzo, 2004 [67] 87.7 40.0 95.9 16.7 84.9 83.2
Schuttler, 2004 [20] 98.0 96.2 99.0 92.7 97.6 96.3
Tanaka, 2000 [68] 97.3 100.0 100.0 98.5 99.0 98.0
Lucejko, 2000 [40] 97.1 99.6 99.6 96.7 98.2 97.2
Catlett, 2019 [41] 100.0 99.2 98.1 100.0 99.5 98.3
Catlett, 2019 [41] 100.0 96.4 90.7 100.0 97.3 96.1
Garcia, 2019 [42] 97.7 97.7 96.9 98.3 97.7 96.7
Mederacke, 2012 [25] 98.3 96.6 98.9 95.0 97.9 96.6
Feng, 2020 [39] 97.0 97.6 92.4 99.1 97.5 96.2
Lin, 2020 [18] 97.3 98.1 99.1 94.5 97.5 96.4
Mean value 95.3 94.0
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Most of studies included genotypes 1a and 1b (29/54), and it was observed a false negative correlation between HCV Ag detection and genotype 3 [29] and high concordance between HCV Ag and HCV RNA results among studies that included HCV patients coinfected with HBV and HIV. Moscato et al. [30] demonstrated a correlation between true positive results and genotype 1b.

A total of 23 studies were included in the univariate pooled sensitivity and specificity estimates. The pooled sensitivity and specificity with 95% CI were 98.82% (95%CI = 98.04%; 99.30%) and 98.95% (95%CI = 97.84%; 99.49%), respectively (Figure 2). Heterogeneity is visually assessed in Figures 2(a) and 2(b). The studies appear to be homogeneous in the overall where I2 was 65% (P = 0.97) for specificity and I2 was 50% (P = 0.99) for sensitivity estimates.

Figure 2.

Figure 2

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(a) Forest plot of HCV Ag assay sensitivity for the diagnosis of active HCV infection compared to HCV RNA test for all samples regardless of HCV Ab status. TP: true positive; FN: false negative; CI: confidence interval. (b) Forest plot of HCV Ag assay specificity for the diagnosis of active HCV infection compared to HCV RNA test for all samples regardless of HCV Ab status. TP: true positive; FN: false negative; CI: confidence interval.

3.4. HCV Antigen for Monitoring Antiviral Therapy

A total of 18 studies used HCV Ag testing to evaluate antiviral treatment (Table 3). Most of studies (15/18) used ECLIA methodology, and only three of them used ELISA [21, 31, 32]. It was not possible to calculate sensitivity and specificity for most of studies. Nine studies used PEG-IFN/ribavirin as antiviral treatment. Nine out of 18 studies used DAA for antiviral treatment. In addition, only 5 reported concordances between HCV and HCV RNA. Regarding the utility of HCV Ag testing and therapy, five studies demonstrated HCV Ag results at 4 weeks and end of treatment and only two assessed SVR. At the end of treatment, sensitivities varied from 50 to 100% while specificities varied from 92.8% to 100%. At week 4 after beginning of treatment, sensitivities of HCV Ag testing varied from 31.25 to 77.9%. High concordance was found between HCV Ag testing and HCV RNA detection after completion of treatment. Those five studies found agreement from 89.7% to 99.75%.

4. Discussion

This review is aimed at evaluating HCV Ag detection test as an alternative to HCV-RNA for the diagnosis of active HCV infection and for the monitoring of antiviral treatment. We concluded that HCV Ag testing can be an alternative to HCV RNA testing for molecular diagnosis of HCV infection.

HCV Ag testing demonstrated pooled sensitivity of 98.82% (95%CI = 98.04%; 99.30%) and specificity of 98.95% (95%CI = 97.84%; 99.49%). ECLIA technology presented higher values of sensitivity and specificity for detecting HCV Ag to identify HCV active cases. However, this technique is more widely used for HCV Ag in comparison to ELISA technique. Galli et al. [33] showed that the ECLIA technique specifically from Abbott Diagnostics Architect HCV Ag, which is the test most commonly used today, detects up to 0.06 pg/ml HCV Ag, whereas older ELISA tests such as Ortho Core antigen detect only samples with 10 pg/ml or more of HCV Ag. Reddy et al. [34] only recruited chronic kidneys and found a sensitivity in HCV Ag detection of only 60% in ELISA tests. It is important to note that this low value may also be related to the clinical condition of these individuals. However, it was not possible to evaluate this information in this review due to few information regarding this topic.

DBS samples were used as biological sample for detecting HCV Ag using ECLIA methodology and showed sensitivity ≤ 87.2% [24, 27, 28] when compared to HCV Ag detection in serum or plasma. Because of this, the use of DBS samples also needs to be further studied to facilitate the diagnosis by detecting HCV Ag. Studies that used serum or plasma with the ECLIA methodology in the diagnosis of HCV Ag showed a sensitivity between 90.4 and 100% compared to HCV RNA detection. Two studies demonstrated lower sensitivities. Florea et al. [35] found 82.4% sensitivity but test demonstrated good performance in patients with HCV RNA ≥ 1000 IU/mL. Fan et al. [36] found 80.2% sensitivity but it was not possible to identify the reasons for this low value.

This study also reviewed several studies that analyzed the use of HCV Ag in monitoring treatment for HCV, with different drugs and at different times of treatment. Most of these studies used ECLIA technique. Gonzalez et al. [21] suggest that ELISA for HCV Ag detection is not used to monitor the end of treatment or an SVR due to the low sensitivity of the test presented in the study (42.5%). Few studies evaluated the concordance between HCV Ag testing and HCV RNA detection to evaluate antiviral treatment, but those studies found values from 89.7% and 95% demonstrating the feasibility of HCV Ag testing to replace HCV RNA detection in low-resource areas. It was also observed that HCV Ag testing has high sensitivity at end of treatment compared to 4 weeks after beginning of treatment. Fan et al. [36] suggested that HCV Ag may be a more sensitive predictor of relapse than HCV RNA after antiviral treatment.

Most of studies that evaluated the accuracy of the HCV Ag test for the diagnosis of HCV were conducted in regions of high HCV prevalence, and this affects the performance of assay to detect HCV acute cases. In the present study, it was observed that sensitivity was not always 100% due to differences in prevalence or population studied. In these cases, such as hemodialysis and people living with HIV, it should be interesting to perform HCV RNA in HCV Ag negative cases to rule out false negative cases [37, 38]. This situation could increase the costs, but it remains a low-cost strategy compared to HCV RNA testing in all subjects. Economic analysis of HCV Ag testing should be relevant in high HCV settings. If the short- and long-term consequences of the HCV Ag test false positives (FPs) and false negatives (FNs) cost less than the extra cost of using the HCV RNA, to use the HCV Ag test will be efficient.

This study presents some limitations such as the evaluation of HIV or HBV coinfection and HCV genotype in meta-analysis results. In addition, it was not possible to determine sensitivity and specificity of HCV Ag testing to evaluate antiviral treatment due to absence of data and few studies have analyzed SVR after treatment with DAAs.

We conclude that HCV Ag detection using ECLIA technique, especially in serum samples, is useful to identify HCV active cases. In addition, this assay presented good results to evaluate antiviral response particularly for PEG-IFN therapy. HCV Ag assay could be an important tool to increase HCV diagnosis in low-resource areas.

Acknowledgments

This research was supported by the Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), the Brazilian National Counsel of Technological and Scientific Development (CNPq), and the Oswaldo Cruz Foundation (FIOCRUZ). FIB and JCM are members of the “Brazil's Fight Against Hepatitis C: Surveillance, Control, and Care” collaborative network, comprised by FGV (Getúlio Vargas Foundation, Brazil), FIOCRUZ (Oswaldo Cruz Foundation), and LSE (London School of Economics and Political Science). The consortium is core funded by the Newton Fund (“Institutional Links” initiative), in partnership with the Brazilian institutions.

Data Availability

All data are available in the manuscript and supplementary materials.

Disclosure

The funders had no role in designing the study and collection, analysis, and interpretation of data and in writing the manuscript.

Conflicts of Interest

The authors declare that they have no competing interests in this section.

Supplementary Materials

Supplementary Materials

Supplementary figures demonstrated the quality of studies. S1 shows the risk of bias, S2 shows the applicability of studies, and S3 gives the QUADAS-2 assessment. Figure S1: risk of bias graph. Figure S2: applicability concern graph. Figure S3: QUADAS-2 assessment tool for studies of diagnostic accuracy.

Click here for additional data file. (128.8KB, pdf)

References

  • 1.Villar L. M., Cruz H. M., Barbosa J. R., Bezerra C. S., Portilho M. M., Scalioni L. P. Update on hepatitis B and C virus diagnosis. World Journal of Virology . 2015;4(4):323–342. doi: 10.5501/wjv.v4.i4.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Martinello M., Hajarizadeh B., Grebely J., Dore G. J., Matthews G. V. Management of acute HCV infection in the era of direct-acting antiviral therapy. Nature Reviews. Gastroenterology & Hepatology . 2018;15(7):412–424. doi: 10.1038/s41575-018-0026-5. [DOI] [PubMed] [Google Scholar]
  • 3.CDC. Testing for HCV infection: an update of guidance for clinicians and laboratorians . 2013. January 2021, http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6218a5.html. [PMC free article] [PubMed]
  • 4.WHO. Guidelines on hepatitis B and C testing . WHO; 2016. January 2021, http://www.who.int/hepatitis/publications/guidelines-hepatitis-c-b-testing/en/ [Google Scholar]
  • 5.Pawlotsky J. M., Negro F., Aghemo A., et al. EASL recommendations on treatment of hepatitis C: Final update of the series☆. Journal of Hepatology . 2020;73(5):1170–1218. doi: 10.1016/j.jhep.2020.08.018. [DOI] [PubMed] [Google Scholar]
  • 6.Jia W., Weng J., Fang C., Li Y. A dynamic model and some strategies on how to prevent and control hepatitis c in mainland China. BMC Infectious Diseases . 2019;19(1):p. 724. doi: 10.1186/s12879-019-4311-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Laperche S., Nübling C. M., Stramer S. L., et al. Sensitivity of hepatitis C virus core antigen and antibody combination assays in a global panel of window period samples. Transfusion . 2015;55(10):2489–2498. doi: 10.1111/trf.13179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Wong X. Z., Gan C. C., Mohamed R., et al. Hepatitis C core antigen testing to diagnose active hepatitis C infection among haemodialysis patients. BMC Nephrology . 2020;21(1):p. 480. doi: 10.1186/s12882-020-02154-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Kumar R., Chan K. P., Ekstrom V. S. M., et al. Hepatitis C virus antigen detection is an appropriate test for screening and early diagnosis of hepatitis C virus infection in at-risk populations and immunocompromised hosts. Journal of Medical Virology . 2021;93(6):3738–3743. doi: 10.1002/jmv.26433. [DOI] [PubMed] [Google Scholar]
  • 10.Tedder R. S., Tuke P., Wallis N., Wright M., Nicholson L., Grant P. R. Therapy-induced clearance of HCV core antigen from plasma predicts an end of treatment viral response. Journal of Viral Hepatitis. . 2013;20(1):65–71. doi: 10.1111/j.1365-2893.2012.01630.x. [DOI] [PubMed] [Google Scholar]
  • 11.Lamoury F. M. J., Soker A., Martinez D., et al. Hepatitis C virus core antigen: a simplified treatment monitoring tool, including for post-treatment relapse. Journal of Clinical Virology . 2017;92:32–38. doi: 10.1016/j.jcv.2017.05.007. [DOI] [PubMed] [Google Scholar]
  • 12.Nguyen L. T., Gray E., O'Leary A., Carr M., de Gascun C. F., Irish Hepatitis C Outcomes Research Network The role of hepatitis C virus core antigen testing in the era of direct acting antiviral therapies: what we can learn from the protease inhibitors. PLoS One . 2016;11(10, article e0163900) doi: 10.1371/journal.pone.0163900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Aghemo A., Degasperi E., de Nicola S., et al. Quantification of core antigen monitors efficacy of direct-acting antiviral agents in patients with chronic hepatitis C virus infection. Clinical Gastroenterology and Hepatology . 2016;14(9):1331–1336. doi: 10.1016/j.cgh.2016.03.035. [DOI] [PubMed] [Google Scholar]
  • 14.Chevaliez S., Feld J., Cheng K., et al. Clinical utility of HCV core antigen detection and quantification in the diagnosis and management of patients with chronic hepatitis C receiving an all-oral, interferon-free regimen. Antiviral Therapy . 2016;23(3):211–217. doi: 10.3851/IMP3042. [DOI] [PubMed] [Google Scholar]
  • 15.Rockstroh J. K., Feld J. J., Chevaliez S., et al. HCV core antigen as an alternate test to HCV RNA for assessment of virologic responses to all-oral, interferon-free treatment in HCV genotype 1 infected patients. Journal of Virological Methods . 2017;245:14–18. doi: 10.1016/j.jviromet.2017.03.002. [DOI] [PubMed] [Google Scholar]
  • 16.Freiman J. M., Tran T. M., Schumacher S. G., et al. Hepatitis C core antigen testing for diagnosis of hepatitis C virus Infection. Annals of Internal Medicine . 2016;165(5):p. 345. doi: 10.7326/M16-0065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Whiting P. F. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Annals of Internal Medicine . 2011;155(8):p. 529. doi: 10.7326/0003-4819-155-8-201110180-00009. [DOI] [PubMed] [Google Scholar]
  • 18.Lin S. F., Tung S.-Y., Wei K.-L., et al. Clinical utility of hepatitis C virus core antigen assay in the monitoring of direct-acting antivirals for chronic hepatitis C. PLoS One . 2020;15(3, article e0229994) doi: 10.1371/journal.pone.0229994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ballardini G., Manzin A., Giostra F., et al. Quantitative liver parameters of HCV infection: relation to HCV genotypes, viremia and response to interferon treatment. Journal of Hepatology . 1997;26(4):779–786. doi: 10.1016/S0168-8278(97)80242-5. [DOI] [PubMed] [Google Scholar]
  • 20.Schüttler C. G., Thomas C., Discher T., et al. Variable ratio of hepatitis C virus RNA to viral core antigen in patient sera. Journal of Clinical Microbiology . 2004;42(5):1977–1981. doi: 10.1128/JCM.42.5.1977-1981.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Gonzalez V., Padilla E., Diago M., et al. Clinical usefulness of total hepatitis C virus core antigen quantification to monitor the response to treatment with peginterferon alpha-2a plus ribavirin. Journal of Viral Hepatitis . 2005;12(5):481–487. doi: 10.1111/j.1365-2893.2005.00628.x. [DOI] [PubMed] [Google Scholar]
  • 22.Murayama A., Sugiyama N., Watashi K., et al. Japanese reference panel of blood specimens for evaluation of hepatitis C virus RNA and core antigen quantitative assays. Journal of Clinical Microbiology . 2012;50(6):1943–1949. doi: 10.1128/JCM.00487-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Wang L., Chen W., Xi W., et al. Utility of enzyme-linked immunosorbent assays to test core antigen in the diagnosis and antiviral therapy management of hepatitis C virus infections. Journal of Medical Virology . 2017;89(7):1235–1240. doi: 10.1002/jmv.24754. [DOI] [PubMed] [Google Scholar]
  • 24.Nguyen T. T., Lemee V., Bollore K., et al. Confirmation of HCV viremia using HCV RNA and core antigen testing on dried blood spot in HIV infected peoples who inject drugs in Vietnam. BMC Infectious Diseases . 2018;18(1):p. 622. doi: 10.1186/s12879-018-3529-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Mederacke I., Potthoff A., Meyer-Olson D., et al. HCV core antigen testing in HIV- and HBV-coinfected patients, and in HCV- infected patients on hemodialysis. Journal of Clinical Virology . 2012;53(2):110–115. doi: 10.1016/j.jcv.2011.11.009. [DOI] [PubMed] [Google Scholar]
  • 26.Long L., Shen T., Gao J., Duan Z., Liang H., Lu F. Effectiveness of HCV core antigen and RNA quantification in HCV-infected and HCV/HIV-1-coinfected patients. BMC Infectious Diseases . 2014;14(1):p. 577. doi: 10.1186/s12879-014-0577-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Mohamed Z., Mbwambo J., Shimakawa Y., et al. Clinical utility of HCV core antigen detection and quantification using serum samples and dried blood spots in people who inject drugs in Dar-es-Salaam, Tanzania. Journal of the International AIDS Society . 2017;20(1):p. 21856. doi: 10.7448/IAS.20.1.21856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Lamoury F. M. J., Hajarizadeh B., Soker A., et al. Evaluation of a hepatitis C virus core antigen assay in plasma and dried blood spot samples. The Journal of Molecular Diagnostics . 2018;20(5):621–627. doi: 10.1016/j.jmoldx.2018.05.010. [DOI] [PubMed] [Google Scholar]
  • 29.Wasitthankasem R., Vichaiwattana P., Auphimai C., et al. HCV core antigen is an alternative marker to HCV RNA for evaluating active HCV infection: implications for improved diagnostic option in an era of affordable DAAs. PeerJ . 2017;5, article e4008 doi: 10.7717/peerj.4008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Moscato G. A., Giannelli G., Grandi B., et al. Quantitative determination of hepatitis C core antigen in therapy monitoring for chronic hepatitis C. Intervirology . 2011;54(2):61–65. doi: 10.1159/000318878. [DOI] [PubMed] [Google Scholar]
  • 31.Soffredini R., Rumi M. G., Parravicini M. L., et al. Serum levels of hepatitis C virus core antigen as a marker of infection and response to therapy. The American Journal of Gastroenterology . 2004;99(9):1738–1743. doi: 10.1111/j.1572-0241.2004.30396.x. [DOI] [PubMed] [Google Scholar]
  • 32.Takahashi M., Saito H., Higashimoto M., Atsukawa K., Ishii H. Benefit of hepatitis C virus core antigen assay in prediction of therapeutic response to interferon and ribavirin combination therapy. Journal of Clinical Microbiology . 2005;43(1):186–191. doi: 10.1128/JCM.43.1.186-191.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Galli C., Julicher P., Plebani M. HCV core antigen comes of age: a new opportunity for the diagnosis of hepatitis C virus infection. Clinical Chemistry and Laboratory Medicine . 2018;56(6):880–888. doi: 10.1515/cclm-2017-0754. [DOI] [PubMed] [Google Scholar]
  • 34.Reddy A. K., Dakshinamurty K. V., Lakshmi V. Utility of HCV core antigen ELISA in the screening for hepatitis C virus infection in patients on hemodialysis. Indian Journal of Medical Microbiology . 2006;24(1):55–57. doi: 10.1016/S0255-0857(21)02473-7. [DOI] [PubMed] [Google Scholar]
  • 35.Florea D., Neaga E., Nicolae I., Maxim D., Popa M., Otelea D. Clinical usefulness of HCV core antigen assay for the management of patients with chronic hepatitis C. Journal of Gastrointestinal and Liver Diseases . 2020;23:393–396. doi: 10.15403/jgld.2014.1121.234.chcv. [DOI] [PubMed] [Google Scholar]
  • 36.Fan Z., Liu J., Wang F., Liu J., Ding X., Liu S. HCV core antigen is a useful predictor during pegylated-interferon/ribavirin therapy in patients with hepatitis C virus genotype 1b. Medicine (Baltimore) . 2019;98(10, article e14795) doi: 10.1097/MD.0000000000014795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Jülicher P., Galli C. Identifying cost-effective screening algorithms for active hepatitis C virus infections in a high prevalence setting. Journal of Medical Economics . 2018;21(1):1–10. doi: 10.1080/13696998.2017.1369983. [DOI] [PubMed] [Google Scholar]
  • 38.Hassanin T. M., Abdelraheem E. M., Abdelhameed S., Abdelrazik M., Fouad Y. M. Detection of hepatitis C virus core antigen as an alternative method for diagnosis of hepatitis C virus infection in blood donors negative for hepatitis C virus antibody. European Journal of Gastroenterology & Hepatology . 2020;32(10):1348–1351. doi: 10.1097/MEG.0000000000001647. [DOI] [PubMed] [Google Scholar]
  • 39.Feng B., Yang R.-F., Jiang H.-J., et al. Correlation analysis of hepatitis C virus core antigen and low viral loads: can core antigen replace nucleic acid test? Clinical and Experimental Medicine . 2020;20(1):131–141. doi: 10.1007/s10238-019-00588-1. [DOI] [PubMed] [Google Scholar]
  • 40.Łucejko M., Tomasiewicz K., Olczak A., et al. Hepatitis C virus core antigen as a possible alternative for evaluation of treatment effectiveness after treatment with direct-acting antivirals. British Journal of Biomedical Science . 2019;76(4):190–194. doi: 10.1080/09674845.2019.1654790. [DOI] [PubMed] [Google Scholar]
  • 41.Catlett B., Lamoury F. M., Bajis S., et al. Evaluation of a hepatitis C virus core antigen assay from venepuncture and dried blood spot collected samples: a cohort study. Journal of Viral Hepatitis . 2019;26(12):1423–1430. doi: 10.1111/jvh.13196. [DOI] [PubMed] [Google Scholar]
  • 42.Pérez-García A., Aguinaga A., Navascués A., Castilla J., Ezpeleta C. Hepatitis C core antigen: diagnosis and monitoring of patients infected with hepatitis C virus. International Journal of Infectious Diseases . 2019;89:131–136. doi: 10.1016/j.ijid.2019.09.022. [DOI] [PubMed] [Google Scholar]
  • 43.Xiang Y., Lai X. F., Chen P., Yang Y. The correlation of HCV RNA and HCV core antigen in different genotypes of HCV. Journal of Clinical Laboratory Analysis . 2019;33(1, article e22632) doi: 10.1002/jcla.22632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.van Tilborg M., al Marzooqi S. H., Wong W. W. L., et al. HCV core antigen as an alternative to HCV RNA testing in the era of direct- acting antivirals: retrospective screening and diagnostic cohort studies. The Lancet Gastroenterology & Hepatology . 2018;3(12):856–864. doi: 10.1016/S2468-1253(18)30271-1. [DOI] [PubMed] [Google Scholar]
  • 45.Adland E., Jesuthasan G., Downs L., et al. Hepatitis virus (HCV) diagnosis and access to treatment in a UK cohort. BMC Infectious Diseases . 2018;18(1):p. 461. doi: 10.1186/s12879-018-3367-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Łucejko M., Flisiak R. Quantitative measurement of HCV core antigen for management of interferon-free therapy in HCV-infected patients. Antiviral Therapy . 2017;23:149–156. doi: 10.3851/IMP3190. [DOI] [PubMed] [Google Scholar]
  • 47.Talal A. H., Chen Y., Zeremski M., et al. Hepatitis C virus core antigen: a potential alternative to HCV RNA testing among persons with substance use disorders. Journal of Substance Abuse Treatment . 2017;78:37–42. doi: 10.1016/j.jsat.2017.04.011. [DOI] [PubMed] [Google Scholar]
  • 48.Loggi E., Galli S., Vitale G., et al. Monitoring the treatment of hepatitis C with directly acting antivirals by serological and molecular methods. PLoS One . 2017;12(11, article e0187755) doi: 10.1371/journal.pone.0187755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Arboledas J. C. A., Guerrero I. P., Rodríguez M. J. B., et al. Hepatitis C virus core antigen in the management of patients treated with new direct-acting antivirals. Diagnostic Microbiology and Infectious Disease . 2017;89(1):29–34. doi: 10.1016/j.diagmicrobio.2017.06.006. [DOI] [PubMed] [Google Scholar]
  • 50.Alonso R., Pérez-García F., Ampuero D., Reigadas E., Bouza E. New direct-acting antivirals for patients with chronic HCV infection: can we monitor treatment using an HCV core antigen assay? Diagnostic Microbiology and Infectious Disease . 2017;87(3):243–246. doi: 10.1016/j.diagmicrobio.2016.11.010. [DOI] [PubMed] [Google Scholar]
  • 51.Pischke S., Polywka S., Proske V. M., et al. Course of hepatitis C virus (HCV) RNA and HCV core antigen testing are predictors for reaching sustained virologic response in liver transplant recipients undergoing sofosbuvir treatment in a real-life setting. Transplant Infectious Disease . 2016;18(1):141–145. doi: 10.1111/tid.12475. [DOI] [PubMed] [Google Scholar]
  • 52.Kim M. N., Kim H. S., Kim J. K., et al. Clinical utility of a new automated hepatitis C virus core antigen assay for prediction of treatment response in patients with chronic hepatitis C. Journal of Korean Medical Science . 2016;31(9):1431–1437. doi: 10.3346/jkms.2016.31.9.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Kamal S. M., Kassim S., el Gohary E., et al. The accuracy and cost-effectiveness of hepatitis C core antigen assay in the monitoring of anti-viral therapy in patients with chronic hepatitis C genotype 4. Alimentary Pharmacology & Therapeutics . 2015;42(3):307–318. doi: 10.1111/apt.13261. [DOI] [PubMed] [Google Scholar]
  • 54.Garbuglia A. R., Lionetti R., Lapa D., et al. The clinical significance of HCV core antigen detection during Telaprevir/Peg- Interferon/Ribavirin therapy in patients with HCV 1 genotype infection. Journal of Clinical Virology . 2015;69:68–73. doi: 10.1016/j.jcv.2015.06.002. [DOI] [PubMed] [Google Scholar]
  • 55.Chevaliez S., Soulier A., Poiteau L., Bouvier-Alias M., Pawlotsky J. M. Clinical utility of hepatitis C virus core antigen quantification in patients with chronic hepatitis C. Journal of Clinical Virology . 2014;61(1):145–148. doi: 10.1016/j.jcv.2014.05.014. [DOI] [PubMed] [Google Scholar]
  • 56.Garbuglia A. R., Monachetti A., Galli C., et al. HCV core antigen and HCV-RNA in HIV/HCV co-infected patients with different HCV genotypes. BMC Infectious Diseases . 2014;14(1):1–9. doi: 10.1186/1471-2334-14-222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Heidrich B., Pischke S., Helfritz F. A., et al. Hepatitis C virus core antigen testing in liver and kidney transplant recipients. Journal of Viral Hepatitis . 2014;21(11):769–779. doi: 10.1111/jvh.12204. [DOI] [PubMed] [Google Scholar]
  • 58.Hadziyannis E., Minopetrou M., Georgiou A., Spanou F., Koskinas J. Is HCV core antigen a reliable marker of viral load? An evaluation of HCV core antigen automated immunoassay. Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology . 2013;26(2):p. 146. [PMC free article] [PubMed] [Google Scholar]
  • 59.Vermehren J., Susser S., Berger A., et al. Clinical utility of the ARCHITECT HCV Ag assay for early treatment monitoring in patients with chronic hepatitis C genotype 1 infection. Journal of Clinical Virology . 2012;55(1):17–22. doi: 10.1016/j.jcv.2012.05.008. [DOI] [PubMed] [Google Scholar]
  • 60.Kesli R., Polat H., Terzi Y., Kurtoglu M. G., Uyar Y. Comparison of a newly developed automated and quantitative hepatitis C virus (HCV) core antigen test with the HCV RNA assay for clinical usefulness in confirming anti-HCV results. Journal of Clinical Microbiology . 2011;49(12):4089–4093. doi: 10.1128/JCM.05292-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Miedouge M., Saune K., Kamar N., Rieu M., Rostaing L., Izopet J. Analytical evaluation of HCV core antigen and interest for HCV screening in haemodialysis patients. Journal of Clinical Virology . 2010;48(1):18–21. doi: 10.1016/j.jcv.2010.02.012. [DOI] [PubMed] [Google Scholar]
  • 62.Ross R. S., Viazov S., Salloum S., Hilgard P., Gerken G., Roggendorf M. Analytical performance characteristics and clinical utility of a novel assay for total hepatitis C virus core antigen quantification. Journal of Clinical Microbiology . 2010;48(4):1161–1168. doi: 10.1128/JCM.01640-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Medhi S., Potukuchi S. K., Polipalli S. K., et al. Diagnostic utility of hepatitis C virus core antigen in hemodialysis patients. Clinical Biochemistry . 2008;41(7-8):447–452. doi: 10.1016/j.clinbiochem.2007.12.024. [DOI] [PubMed] [Google Scholar]
  • 64.Bouzgarrou N., Fodha I., Othman S. B., et al. Evaluation of a total core antigen assay for the diagnosis of hepatitis C virus infection in hemodialysis patients. Journal of Medical Virology . 2005;77(4):502–508. doi: 10.1002/jmv.20485. [DOI] [PubMed] [Google Scholar]
  • 65.Massaguer A., Forns X., Costa J., et al. Performance of hepatitis C virus core antigen immunoassay in monitoring viral load after liver transplantation. Transplantation . 2005;79(10):1441–1444. doi: 10.1097/01.TP.0000158356.81437.FA. [DOI] [PubMed] [Google Scholar]
  • 66.Fabrizi F., Lunghi G., Aucella F., et al. Novel assay using total hepatitis C virus (HCV) core antigen quantification for diagnosis of HCV infection in dialysis patients. Journal of Clinical Microbiology . 2005;43(1):414–420. doi: 10.1128/JCM.43.1.414-420.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Lorenzo J., Castro A., Aguilera A., et al. Total HCV core antigen assay: a new marker of HCV viremia and its application during treatment of chronic hepatitis C. Journal of Virological Methods . 2004;120(2):173–177. doi: 10.1016/j.jviromet.2004.05.002. [DOI] [PubMed] [Google Scholar]
  • 68.Tanaka E., Ohue C., Aoyagi K., et al. Evaluation of a new enzyme immunoassay for hepatitis C virus (HCV) core antigen with clinical sensitivity approximating that of genomic amplification of HCV RNA. Hepatology . 2000;32(2):388–393. doi: 10.1053/jhep.2000.9112. [DOI] [PubMed] [Google Scholar]
  • 69.Yuksel P., Caliskan R., Ergin S., et al. New approaches to in vitro diagnosis of hepatitis C infection a reason for post transfusion hepatitis: Diagnostic value of determination of hepatitis C virus core antigen. Transfusion and Apheresis Science . 2011;45(3):247–250. doi: 10.1016/j.transci.2011.10.002. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Materials

Supplementary figures demonstrated the quality of studies. S1 shows the risk of bias, S2 shows the applicability of studies, and S3 gives the QUADAS-2 assessment. Figure S1: risk of bias graph. Figure S2: applicability concern graph. Figure S3: QUADAS-2 assessment tool for studies of diagnostic accuracy.

Click here for additional data file. (128.8KB, pdf)

Data Availability Statement

All data are available in the manuscript and supplementary materials.

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